Compound useful for manufacturing salacinol, method for manufacturing the compound, method for manufacturing salacinol, methods for protecting and deprotecting diol group, and protective agent for diol group

ABSTRACT

(In the formula, each of R1a and R1b is a hydrogen atom or a hydroxy protective group; R2 is a hydroxy group or the like; and R3 is a hydroxy group or the like.)

The present application is a Divisional of U.S. application Ser. No.15/709,794, filed Sep. 20, 2017, which is a Divisional of U.S.application Ser. No. 15/268,829, filed Sep. 19, 2016 which is acontinuation of PCT/JP2015/58197 filed on Mar. 19, 2015 and claimspriority under 35 U.S.C. § 119 of Japanese Patent Application No.57961/2014 filed on Mar. 20, 2014, the disclosures of which areincorporated herein by reference.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The present invention relates to a compound useful for manufacturingsalacinol and a method for manufacturing the compound. The presentinvention also relates to a method for manufacturing salacinol, methodsfor protecting and deprotecting a diol group, and a protective agent fora diol group.

2. Description of the Related Art

In traditional Indian medicine, Salacia reticulata which is a climbingtree of the genus Salacia is used for treating diabetes. Salacinol is acomponent contained in plants of the genus Salacia such as Salaciareticulata and has a strong α-glucosidase inhibitory activity(Tetrahedron Letters, Vol. 38, No. 48., pp. 8367-8370 (1997)). Salacinolis obtained from, for example, extracts of plants of the genus Salacia(JP3030008B). However, the supply of plants of the genus Salacia issmall, and it is difficult to easily obtain the plants. Therefore,methods for manufacturing salacinol and analogs thereof by synthesis arebeing investigated in various ways (JP5053494B, JP4939934B, andJP2002-179673A).

JP5053494B describes a manufacturing method in which a cyclic sulfuricacid ester protected with a benzylidene group is reacted with athioarabinitol derivative protected with a benzyl group.

JP4939934B describes a manufacturing method in which a cyclic sulfuricacid ester protected with a benzylidene group is reacted with athioarabinitol derivative protected with a benzyl group.

JP2002-179673A describes a manufacturing method in which a cyclicsulfuric acid ester protected with an isopropylidene group is reactedwith thio-D-arabinitol.

In a case where organic synthesis is performed using a compound having afunctional group such as an amino group, a hydroxy group, or a carboxygroup, in order to prevent the functional group from affecting thereaction, generally, the functional group is protected. Furthermore, ina case where the number of functional groups is 2 or greater, in orderto selectively cause only an intended functional group to react, otherfunctional groups are protected.

A protective group not only needs to stably protect a target functionalgroup but also needs to be easily removed if necessary. Therefore, inorganic synthesis, it is important to deprotect only a protective groupbonded to a specific functional group under appropriate conditions.

For example, as protective groups for an amino group, a hydroxy group,or a carboxy group, various protective groups have been developed(Protective Groups in Organic Synthesis, 4^(th) edition, John Wiley &Sons, INC (2007)). Furthermore, as protective groups for a 1,2-diolgroup or a 1,3-diol group (hereinafter, referred to as a “diol group” insome cases), a cyclic acetal, a cyclic ketal, a cyclic orthoester andthe like are known.

As a protective group for a diol group, an alkoxycarbonylethylidenegroup is known (Organic Letters, Vol. 2, No. 18, pp. 2809-2811 (2000)).

Meanwhile, a method for manufacturing diethyl2-(5-pentyl-1,3-dioxan-2-yl)malonate by reacting2-(hydroxymethyl)heptanol with diethyl ethoxymethylene malonate in thepresence of p-toluenesulfonic acid is known (DE19525314B).

SUMMARY OF THE INVENTION

The method described in JP5053494B has defects such as (1) it has a lowyield, and (2) a complicated operation is required because ahydrogenation reaction is used as a deprotection reaction. This is not asatisfactory method.

The method described in JP4939934B has defects such as (1)hexafluoroisopropanol harmful to humans and imposing a greatenvironmental load is sued as a reaction solvent. This is not asatisfactory method.

The method described in JP2002-179673A had defects such as (1) it has alow yield, and (2) the reaction time is long. This is not a satisfactorymethod.

Furthermore, as described in Organic Letters, Vol 2, No. 18, pp.2809-2811 (2000), for example, a diol group can be protected with analkoxycarbonylethylidene group in the presence of a base. However, thedeprotection reaction has defects such as (1) an excess of base isnecessary, and (2) heating is required. In addition, the types ofprotective group for a diol group are less diverse than the types ofprotective group for a hydroxy group.

In DE19525314B, the obtained diethyl2-(5-pentyl-1,3-dioxan-2-yl)malonate is then reduced and derivatizedinto other compounds. This method does not aim to protect a diol group.

The methods for manufacturing salacinol in the related art have problemssuch as (1) they have a low yield, (2) a complicated operation isrequired, (3) a solvent harmful to humans and imposing a greatenvironmental load is used, and (4) the reaction time is long.Therefore, there is a strong demand for a better industrialmanufacturing method of salacinol and methods for protecting anddeprotecting a diol group.

An object of the present invention is to provide a novel compound usefulfor manufacturing salacinol and a novel method for manufacturingsalacinol.

Another object of the present invention is to provide methods forprotecting and deprotecting a diol group and a protective agent for adiol group that are useful for manufacturing salacinol or the like.

Under the circumstances described above, the inventors of the presentinvention repeated intensive investigation. As a result, they obtainedknowledge that a compound represented by Formula (1) and a compoundrepresented by Formula (7a) are intermediates useful for manufacturingsalacinol. The inventors of the present invention also obtainedknowledge that salacinol can be industrially manufactured from acompound represented by Formula (1a) and a compound represented byFormula (7a). Furthermore, the inventors of the present invention foundmethods for protecting and deprotecting a diol group that are useful formanufacturing salacinol or the like. Based on the above knowledge, theinventors accomplished the present invention.

The present invention provides the following.

[1] A compound represented by Formula (1),

(in the formula, R^(1a) and R^(1b) are the same as or different fromeach other and each represent a hydrogen atom or a carboxy protectivegroup; and each of R² and R³ is a hydroxy group, R² is a grouprepresented by Formula (2) and R³ is a group represented by Formula (3),

(in the formula, R^(4a), R^(4b), and R^(4c) are the same as or differentfrom each other and each represent a hydrogen atom or a hydroxyprotective group; and * represents a binding position), and

(in the formula, * has the same definition as described above), or R²and R³ are bonded to each other and represent a group represented byFormula (4),*—O—X¹—O—*  (4)

(in the formula, X¹ is a group represented by Formula (5) or a grouprepresented by Formula (6); and * has the same definition as describedabove).

(in the formula, R⁵ is an aryl group which may be substituted; and * hasthe same definition as described above), and

(in the formula, * has the same definition as described above)).

[2] The compound described in [1], in which R^(1a) and R^(1b) are thesame as or different from each other and each represent a carboxyprotective group.

[3] The compound described in [1] and [2], in which each of R² and R³ isa hydroxy group.

[4] The compound described in [1] or [2], in which R² is a grouprepresented by Formula (2); and R³ is a group represented by Formula(3),

(in the formula, R^(4a), R^(4b), and R^(4c) have the same definition asdescribed above), and

(in the formula, * has the same definition as described above).

[5] The compound described in [1] or [2], in which R² and R³ are bondedto each other and represent a group represented by Formula (4),*—O—X¹—O—*  (4)

(in the formula, each of X¹ and * have the same definition as describedabove).

[6] The compound described in [1], [2], or [5], in which R⁵ is a phenylgroup which may be substituted

[7] The compound described in [1] that is a compound selected fromdimethyl2-((4aS,8aR)-6-phenyltetrahydro[1,3]dioxino[5,4-d][1,3]dioxin-2-yl)malonate,dimethyl2-((4R,5S)-5-hydroxy-4-(hydroxymethyl)-1,3-dioxan-2-yl)malonate,dimethyl2-((4aR,8aS)-2,2-dioxidotetrahydro[1,3]dioxino[5,4-d][1,3,2]dioxathiin-6-yl)malonate,(4S,5S)-4-(((2R,3S,4S)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-ium-1-yl)methyl-2-(1,3-dimethoxy-1,3-dioxopropan-2-yl)-1,3-dioxan-5-yl sulfate,(4S,5S)-4-(((1S,2R,3S,4S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)tetrahydro-1H-thiophen-1-ium-1-yl)methyl)-2-(1,3-dimethoxy-1,3-dioxopropan-2-yl)-1,3-dioxan-5-ylsulfate,(4S,5S)-4-(((1S,2R,3S,4S)-3,4-bis((4-methoxybenzyl)oxy)-2-(((4-methoxybenzyl)oxy)methyl)tetrahydro-1H-thiophen-1-ium-1-yl)methyl)-2-(1,3-dimethoxy-1,3-dioxopropan-2-yl)-1,3-dioxan-5-ylsulfate, diethyl2-((4aS,8aR)-6-phenyltetrahydro[1,3]dioxino[5,4-d][1,3]dioxin-2-yl)malonate,diethyl 2-((4R,5S)-5-hydroxy-4-(hydroxymethyl)-1,3-dioxan-2-yl)malonate,diethyl2-((4aR,8aS)-2,2-dioxidotetrahydro[1,3]dioxino[5,4-d][1,3,2]dioxathiin-6-yl)malonate,and(4S,5S)-2-(1,3-diethoxy-1,3-dioxopropan-2-yl)-4-(((2R,3S,4S)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-ium-1-yl)methyl)-1,3-dioxan-5-ylsulfate.

[8] A method for manufacturing salacinol, comprising: obtaining acompound represented by Formula (1b) by reacting a compound representedby Formula (1a) with a compound represented by Formula (7),

(in the formula, each of R^(1a) and R^(1b) has the same definition asdescribed above),

(in the formula, each of R^(4a), R^(4b), and R^(4c) has the samedefinition as described above), and

(in the formula, each of R^(1a), R^(1b), R^(4a), R^(4b), and R^(4c) hasthe same definition as described above); and then

subjecting the compound represented by Formula (1b) to a deprotectionreaction.

[9] The manufacturing method described in [8], in which each of R^(1a)and R^(1b) is a carboxy protective group; and each of R^(4a), R^(4b),and R^(4c) is a hydrogen atom.

[10] A method for manufacturing salacinol, comprising: obtaining acompound represented by Formula (1c) by reacting a compound representedby Formula (8) with a compound represented by Formula (9).

(in the formula, R⁵ has the same definition as described above),

(in the formula, R⁶ is a C₁₋₆ alkyl group which may be substituted; andeach of R^(1a) and R^(1b) has the same definition as described above),and

(in the formula, each of R^(1a), R^(1b), and R⁵ has the same definitionas described above);

then obtaining a compound represented by Formula (1d) by subjecting thecompound represented by Formula (1c) to a deprotection reaction,

(in the formula, each of R^(1a) and R^(1b) has the same definition asdescribed above);

then obtaining a compound represented by Formula (1a) by reacting thecompound represented by Formula (1d) with a sulfur-containing compoundand then subjecting the resulting compound to an oxidation reaction ifnecessary.

(in the formula, each of R^(1a) and R^(1b) has the same definition asdescribed above);

then obtaining a compound represented by Formula (1b) by reacting thecompound represented by Formula (1a) with a compound represented byFormula (7),

(in the formula, each of R^(4a), R^(4b), and R^(4c) has the samedefinition as described above), and

(in the formula, each of R^(1a), R^(1b), R^(4a), R^(4b), and R^(4c) hasthe same definition as described above); and then

subjecting the compound represented by Formula (1b) to a deprotectionreaction.

[11] The manufacturing method described in [10], in which R⁵ is a phenylgroup which may be substituted.

[12] The manufacturing method described in [10] or [11], in which eachof R^(1a) and R^(1b) is a carboxy protective group; and each of R^(4a),R^(4b), and R^(4c) is a hydrogen atom.

[13] The compound represented by Formula (7a),

(in the formula, R^(4ba) is a p-toluoyl group).

[14] A method for manufacturing a compound represented by Formula (7b),comprising:

obtaining a compound represented by Formula (12) by reacting a compoundrepresented by Formula (10) with a compound represented by Formula (11),

(in the formula, R⁷ is a C₁₋₃ alkyl group which may be substituted),R^(4ba)-L¹  (11)

(in the formula, L¹ is a leaving group; and R^(4ba) has the samedefinition as described above), and

in the formula, each of R^(4ba) and R⁷ has the same definition asdescribed above);

Then obtaining a compound represented by Formula (7a) by reacting thecompound represented by Formula (12) with an acid and then subjectingthe resulting compound to a reduction reaction,

(in the formula, R^(4ba) has the definition as described above); andthen

subjecting the compound represented by Formula (7a) to a deprotectionreaction.

[15] A method for manufacturing a compound represented by Formula (7b),comprising:

obtaining a compound represented by Formula (15) by reacting a compoundrepresented by Formula (13) with a compound represented by Formula (14),

(in the formula, R⁷ has the same definition as described above),R⁸-L²  (14)

(in the formula, R⁸ is a C₁₋₃ alkylsulfonyl group which may besubstituted or an arylsulfonyl group which may be substituted; and L² isa leaving group), and

(in the formula, each of R⁷ and R⁸ has the same definition as describedabove);

then obtaining a compound represented by Formula (17) by reacting thecompound represented by Formula (15) with a compound represented byFormula (16)R⁹—S⁻K⁺  (16)

(in the formula, R⁹ is an acyl group which may be substituted), and

(in the formula, each of R⁷, R⁸, and R⁹ has the same definition asdescribed above);

then obtaining a compound represented by Formula (18) by reacting thecompound represented by Formula (17) with a base,

(in the formula, each of R⁷ and R⁸ has the same definition as describedabove);

then obtaining a compound represented by Formula (10) by subjecting thecompound represented by Formula (15) to a deprotection reaction,

(in the formula, R⁷ has the same definition as described above);

then obtaining a compound represented by Formula (12) by reacting thecompound represented by Formula (10) with a compound represented byFormula (11),R^(4ba)-L¹  (11)

(in the formula, each of R^(4ba) and L¹ has the same definition asdescribed above), and

(in the formula, each of R^(4ba) and R⁷ has the same definition asdescribed above);

then obtaining a compound represented by Formula (7a) by reacting thecompound represented by Formula (12) with an acid and then subjectingthe resulting compound to a reduction reaction,

(in the formula, R^(4ba) has the same definition as described above);and then

subjecting the compound represented by formula (7a) to a deprotectionreaction.

[16] A method for protecting a 1,2-diol group or a 1,3-diol group,comprising reacting a 1,2-diol group or a 1,3-diol group with a grouprepresented by Formula (19) in the presence of a base,

(in the formula, each of R^(1a), R^(1b), and * has the same definitionas described above).

[17] A method for protecting a 1,2-diol group or a 1,3-diol group,comprising manufacturing a compound represented by Formula (21) byreacting a 1,2-diol group or a 1,3-diol group of a compound representedby Formula (20) with a compound represented by Formula (9) in thepresence of a base,HO—Y¹—OH  (20)

(in the formula, Y¹ is a C₂₋₃ alkylene group which may be substituted),

(in the formula, each of R^(1a), R^(1b), and R⁶ has the same definitionas described above), and

(in the formula, each of R^(1a), R^(1b), and Y¹ has the same definitionas described above).

[18] A protective agent for a 1,2-diol group or a 1,3-diol group,comprising a compound represented by Formula (9),

(in the formula, each of R^(1a), R^(1b), and R⁶ has the same definitionas described above).

[19] A method for deprotecting a protected 1,2-diol group or 1,3-diolgroup, comprising reacting a 1,2-diol group or a 1,3-diol groupprotected with a group represented by Formula (19) with a base,

(in the formula, each of R^(1a), R^(1b), and * has the same definitionas described above).

[20] A method for deprotecting a protected 1,2-diol group or 1,3-diolgroup, comprising manufacturing a compound represented by Formula (20)by reacting a compound which is represented by Formula (21) and has aprotected 1,2-diol group or a protected 1,3-diol group with a base,

(in the formula, each of R^(1a), R^(1b), and Y¹ has the same definitionas described above), andHO—Y¹˜OH  (20)

(in the formula, Y¹ has the same definition as described above).

The compound of the present invention is useful as an intermediate formanufacturing salacinol. The manufacturing method of the presentinvention is useful as a method for manufacturing salacinol.Furthermore, the protective group for a diol group of the presentinvention is a novel protective group, and the protective group and themethods of the present invention are useful as a protective group for adiol group and as methods for protecting and deprotecting a diol group.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Hereinafter, the present invention will be specifically described.

In the present invention, unless otherwise specified, % means masspercentage.

In the present invention, unless otherwise specified, each term has thefollowing meaning.

A halogen atom means a fluorine atom, a chlorine atom, a bromine atom oran iodine atom.

A C₁₋₃ alkyl group means a methyl, ethyl, propyl, or isopropyl group.

A C₁₋₆ alkyl group means a linear or branched C₁₋₆ alkyl group such asmethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, pentyl, and hexyl groups.

A C₂₋₆ alkenyl group means a linear or branched C₂₋₆ alkenyl group suchas vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl,1,3-butadienyl, pentenyl, and hexenyl groups.

A C₂₋₃ alkylene group means an ethylene or propylene group or the like.

An aryl group means a phenyl or naphthyl group or the like.

An ar-C₁₋₆ alkyl group means benzyl, diphenylmethyl, trytyl, phenethyl,and naphthylmethyl groups or the like.

A C₁₋₆ alkoxy group means a linear or branched C₁₋₆ alkoxy group such asmethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,tert-butoxy, pentyloxy, and hexyloxy groups.

A C₁₋₆ alkoxy C₁₋₆ alkyl group means methoxymethyl and 1-ethoxyethylgroups or the like.

A C₂₋₆ alkanoyl group means a linear or branched C₂₋₆ alkanoyl groupsuch as acetyl, propionyl, valeryl, isovaleryl, and pivalolyl groups.

An aroyl group means a benzoyl or naphthyl group, or the like.

An acyl group means a formyl group, a C₁₋₆ alkanoyl group, an aroylgroup, or the like.

A C₁₋₆ alkoxycarbonyl group means a linear or branched C₁₋₆alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, tert-butoxycarbonyl, and 1,1-dimethylpropoxycarbonylgroups.

An aryloxycarbonyl group means a phenyloxycarbonyl ornaphthyloxycarbonyl group or the like.

A C₁₋₆ alkylamino group means a linear or branched C₁₋₆ alkylamino groupsuch as methylamino, ethylamino, propylamino, isopropylamino,butylamino, sec-butylamino, tert-butylamino, pentylamino, and hexylamino groups.

A di(C₁₋₆ alkyl)amino group means a linear or branched di(C₁₋₆alkyl)amino group such as dimethylamino, diethylamino, dipropylamino,diisopropylamino, dibutylamino, di(tert-butyl)amino, dipentylaminodihexylamino, (ethyl)(methyl)amino, and (methyl)(propyl)amino groups.

A C₁₋₆ alkylthio group means methylthio, ethylthio, propylthio groups orthe like.

A C₁₋₃ alkylsulfonyl group means methylsulfonyl and ethylsulfonyl groupsor the like.

A C₁₋₆ alkylsulfonyl group means methylsulfonyl, ethylsulfonyl, andpropynylsulfonyl groups or the like.

An arylsulfonyl group means a benzenesulfonyl, p-toluenesulfonyl, ornaphthalenesulfonyl group or the like.

A C₁₋₆ alkylsulfonyloxy group means methylsulfonyloxy, ethylsulfonyloxy,and propylsulfonyloxy groups or the like.

An arylsulfonyloxy group means a benzenesulfonyloxy,p-toluenesulfonyloxy or naphthalenesulfonyloxy group or the like.

A monocyclic nitrogen-containing heterocyclic group means azetidinyl,pyrrolidinyl, pyrrolinyl, pyrrolyl, piperidyl, tetrahydropyridyl,pyridyl, homopiperidinyl, octahydroazocinyl, pyrazolyl, piperazinyl,pyrazinyl, pyridazinyl, pyrimidinyl, homopiperazinyl, triazolyl, andtetrazolyl groups or the like that contain only a nitrogen atom as aheteroatom forming a ring.

A monocyclic oxygen-containing heterocyclic group means atetrahydrofuranyl, furanyl, tetrahydropyranyl, or pyranyl group or thelike.

A monocyclic sulfur-containing heterocyclic group means a thienyl groupor the like.

A monocyclic nitrogen-oxygen-containing heterocyclic group meansoxazolyl, isoxazolyl, oxadiazolyl, and morpholinyl groups or the likethat contain only a nitrogen atom and an oxygen atom as heteroatomsforming a ring.

A monocyclic nitrogen-sulfur-containing heterocyclic group meansthiazolyl, isothiazolyl, thiadiazolyl, thiomorpholinyl,1-oxidothiomorpholinyl, and 1,1-dioxidothiomorpholinyl groups or thelike that contain only a nitrogen atom and sulfur atom as heteroatomsforming a ring.

A monocyclic heterocyclic group means a monocyclic nitrogen-containingheterocyclic group, a monocyclic oxygen-containing heterocyclic group, amonocyclic sulfur-containing heterocyclic group, a monocyclicnitrogen-oxygen-containing heterocyclic group, a monocyclicnitrogen-sulfur-containing heterocyclic group, or the like.

A bicyclic nitrogen-containing heterocyclic group means indolinyl,indolyl, isoindolinyl, isoindolyl, benzimidazolyl, indazolyl,benzotriazolyl, quinolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,isoquinolinyl, quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl,dihydroquinoxalinyl, quinoxalinyl, naphthyridinyl, purinyl, pteridinyl,and quinuelidinyl groups or the like that contain only a nitrogen atomas a heteroatom forming a ring.

A bicyclic oxygen-containing heterocyclic group means2,3-dihydrobenzofuranyl, benzofuranyl, isobenzofuranyl,1,3-benzodioxanyl, and 1,4-benzodioxanyl groups or the like that containonly an oxygen atom as a heteroatom forming a ring.

A bicyclic sulfur-containing heterocyclic group means2,3-dihydrobenzothienyl and enzothienyl groups or the like that containonly a sulfur atom as a heteroatom forming a ring.

A bicyclic nitrogen-oxygen-containing heterocyclic group meansbenzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzomorpholinyl,dihydropyranopyridyl, dihydrodioxinopyridyl, and dihydropyridooxazinylgroups or the like that contain only a nitrogen atom and an oxygen atomas heteroatoms forming a ring.

A bicyclic nitrogen-sulfur-containing heterocyclic group meansbenzothiazolyl, benzisothiazolyl, and benzothiadiazolyl groups or thelike that contain only a nitrogen atom and a sulfur atom as heteroatomsforming a ring.

A bicyclic heterocyclic group means a bicyclic nitrogen-containingheterocyclic group, a bicyclic oxygen-containing heterocyclic group, abicyclic sulfur-containing heterocyclic group, a bicyclicnitrogen-oxygen-containing heterocyclic group, a bicyclicnitrogen-sulfur-containing heterocyclic group, or the like.

A heterocyclic group means a monocyclic or bicyclic heterocyclic group.

A C₃₋₈ cycloalkyl ring means a cyclopropane, cyclobutane, cyclopentane,cyclohexane, cycloheptane, or cyclooctane ring.

A C₅₋₈ cycloalkyl ring means a cyclopentane, cyclohexane, cycloheptane,or cyclooctane ring.

A non-aromatic nitrogen-containing heterocyclic ring means azetidine,pyrrolidine, piperidine, homopiperidine, piperazine, and homopiperazinerings or the like that contain only a nitrogen atom as a heteroatomforming a ring.

A non-aromatic oxygen-containing heterocyclic ring means oxetane,tetrahydrofuran, tetrahydropyran, 1,3-dioxane, and 1,4-dioxane rings orthe like that contain only an oxygen atom as a heteroatom terming aring.

A non-aromatic sulfur-containing heterocyclic means atetrahydrothiophene ring, or the like.

A non-aromatic nitrogen-oxygen-containing heterocyclic ring meansmorpholine and oxazepam rings or the like that contain only a nitrogenatom and a sulfur atom as heteroatoms forming a ring.

A non-aromatic nitrogen-sulfur-containing heterocyclic ring means athiomorpholine ring or the like.

A non-aromatic heterocyclic ring means a non-aromaticnitrogen-containing heterocyclic ring, a non-aromatic oxygen-containingheterocyclic ring, a non-aromatic sulfur-containing heterocyclic ring, anon-aromatic nitrogen-oxygen-containing heterocyclic ring, or anon-aromatic nitrogen-sulfur-containing heterocyclic ring.

A silyl group means a trimethylsilyl, triethylsilyl, triisopropylsilyl,tributylsilyl, tert-butyldimethylsilyl, or tert-butyldiphenylsilyl groupor the like.

A leaving group means a halogen atom, a C₁₋₆ alkylsulfonyloxy group, oran arylsulfonyloxy group. These groups may be substituted with one ormore groups selected from a substituent group B.

A hydroxy protective group includes all of the groups that can be usedas general protective groups for a hydroxy group, and examples thereofinclude the groups described in W. Greene et al, Protective Groups inOrganic Synthesis, 4^(th) edition, pp, 16-366, 2007, John Wiley & Sons,INC.

Specific examples thereof include a C₁₋₆ alkyl group group, a C₂₋₆alkenyl group, an ar-C₁₋₆ alkyl group, a C₁₋₆ alkoxy C₁₋₆ alkyl group,an acyl group, a C₁₋₆ alkoxycarbonyl group, a C₁₋₆ alkylsulfonyl group,an arylsulfonyl group, a tetrahydrofuranyl group, a tetrahydropranylgroup, a silyl group, and the like. These groups may be substituted withone or more groups selected from a substituent group A.

An amino protective group includes all of the groups that can be used asgeneral protective groups for an amino group, and examples thereofinclude the groups described in W. Greene et al, Protective Groups inOrganic Synthesis, 4^(th) edition, pp. 696-926, 2007, John Wiley & Sons,INC.

Specific examples thereof include an ar-C₁₋₆ alkyl group, a C₁₋₆ alkoxyC₁₋₆ alkyl group, a C₁₋₆ alkoxycarbonyl group, an aryloxycarbonyl group,a C₁₋₆ alkylsulfonyl group, an arylsulfonyl group, a silyl group, andthe like. These groups may be substituted with one or more groupsselected from a substituent group A.

A carboxy protective group includes all of the groups that can be usedas general protective groups for a carboxy group, and examples thereofinclude w. Greene et al, Protective Groups in Organic Synthesis, 4^(th)edition, pp, 533-646, 2007, John Wiley & Sons, INC.

Specific examples thereof include a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, an aryl group, an ar-C₁₋₆ alkyl group, a C₁₋₆ alkoxy alkyl group,a silyl group, and the like. These groups may be substituted with one ormore groups selected from a substituent group A.

In the present specification, each substituent group means thefollowing.

Substituent group A: a halogen atom, a cyano group, a nitro group, anamino group which may be protected, a hydroxy group which may beprotected, a carboxy group which may be protected, a C₁₋₆ group whichmay be substituted with one or more groups selected from a substituentgroup B, an aryl group which may be substituted with one or more groupsselected from a substituent group B, a C₁₋₆ alkoxy group which may besubstituted with one or more groups selected from a substituent group B,a C₁₋₆ alkylamino group which may be substituted with one or more groupsselected from a substituent group B, a di(C₁₋₆ alkyl)amino group whichmay be substituted with one or more groups selected from a substituentgroup B, and a C₁₋₆ alkylthio group which may be substituted with one ormore groups selected from a substituent group B.

Substituent group B: a halogen atom, a cyano group, a nitro group, aC₁₋₆ alkyl group which may be substituted with a halogen atom, an arylgroup which may be substituted with a halogen atom, and a C₁₋₆ alkoxygroup which may be substituted with a halogen atom.

Examples of aliphatic hydrocarbons induce pentane, hexane, cyclohexane,and the like.

Examples of halogenated hydrocarbons include methylene chloride,chloroform, 1,2-dichloroethane, and the like.

Examples of alcohols include methanol, ethanol, propanol, 2-propanol,butanol, 2-methyl-2-propanol, and the like.

Examples of ethers include diethyl ether, diisopropylether, dioxane,tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethyleneglycol dimethyl ether, diethylene glycol diethyl ether, and the like.

Examples of esters include methyl acetate, ethyl acetate, propylacetate, isopropyl acetate, butyl acetate, and the like.

Examples of ketones include acetone, 2-butanone, 4-methyl-2-pentanone,and the like.

Examples of nitriles include acetonitrile and the like.

Examples of amides include N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone, and the like.

Examples of sulfoxides include dimethylsulfoxide and the like.

Examples of aromatic hydrocarbons include benzene, toluene, xylene, andthe like.

Examples of ureas include 1,3-dimethyl-2-imidazolidinone and the like.

An inorganic acid means hydrochloric acid, hydrobromic acid, nitricacid, phosphoric acid, sulfuric acid, boric acid, hydrofluoric acid, orthe like.

An organic acid means formic acid, acetic acid, trifluoroacetic acid,phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid,citric acid, succinic acid, malic acid, methanesulfonic acid,benzenesulfonic acid, p-toluene sulfonic acid, camphorsulfonic acid, orthe like.

An acid means an inorganic acid or an organic acid.

An inorganic base means sodium hydroxide, potassium hydroxide, sodiumhydrogen carbonate, sodium carbonate, potassium carbonate, cesiumcarbonate, tripotassium phosphate, tert-butoxypotassium, sodiumethoxide, sodium methoxide, sodium hydride, or the like.

An organic base means propylamine, dimethylamine, dibutylamine,triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine,4-dimethylaminopyridine, tetraethylammonium hydroxide,diazabicycloundecene, diazabicyclononene, guanidine, N-methylimidazole,morpholine, N-methylmorpholine, or the like.

A base means an inorganic base or an organic base.

The aryl group represented by R⁵ may be substituted with one or moregroups selected from the substituent group A.

The C₁₋₆ alkyl group represented by R⁶ may be substituted with one ormore groups selected from the substituent group A.

The C₁₋₃ alkyl group represented by R⁷ may be substituted with one ormore groups selected from the substituent group A.

Each of the C₁₋₃ alkylsulfonyl group and the arylsulfonyl grouprepresented by R⁸ may be substituted with one or more groups selectedfrom the substituent group A.

The acyl group represented by R⁹ may be substituted with one or moregroups selected from the substituent group A.

The C₂₋₃ alkylene group represented by Y¹ may be substituted with one ormore groups selected from the substituent A.

Preferred examples of the compound represented by Formula (1 include thefollowing compounds.

The compound represented by Formula (1) is preferably a compound inwhich each of R^(1a) and R^(1b) is a carboxy protective group.

The carboxy protective group represented by R^(1a) and R^(1b) ispreferably a C₁₋₆ alkyl group which may be substituted with one or moregroups selected from the substituent group A, a C₂₋₆ alkenyl group whichmay be substituted with one or more groups selected from the substituentgroup A, an aryl group which may be substituted with one or more groupsselected from the substituent group A, an ar-C₁₋₆ alkyl group which maybe substituted with one or more groups selected from the substituentgroup A, a C₁₋₆ alkoxy C₁₋₆ alkyl group which may be substituted withone or more groups selected from the substituent group A, or a silylgroup which may be substituted with one or more groups selected from thesubstituent group A, more preferably a C₁₋₆ alkyl group which may besubstituted with one or more groups selected from the substituent groupA, even more preferably a C₁₋₆ alkyl group, and particularly preferablya C₁₋₃ alkyl group.

The compound represented by Formula (1) is preferably a compound inwhich each of R² and R³ is a hydroxy group.

The compound represented by Formula (1) is preferably a compound inwhich R² is a group represented by Formula (2), and R³ is a grouprepresented by Formula (3).

(In the formula, each of R^(4a), R^(4b), R^(4c), and * has the samedefinition as described above.)

(In the formula, * has the same definition as described above.)

The compound represented by Formula (1) is preferably a compound inwhich each of R^(4a), R^(4b), and R^(4c) is a hydrogen atom, a C₁₋₆alkyl group which may be substituted with one or more groups selectedfrom the substituent group A, a C₂₋₆ alkenyl group which may besubstituted with one or more groups selected from the substituent groupA, an ar-C₁₋₆ alkyl group which may be substituted with one or moregroups selected from the substituent group A, a C₁₋₆ alkoxy C₁₋₆ alkoxygroup which may be substituted with one or more groups selected from thesubstituent group A, an acyl group which may be substituted with one ormore groups selected from the substituent group A, a C₁₋₆ alkoxycarbonylgroup which may be substituted with one or more groups selected from thesubstituent group A, a C₁₋₆ alkylsulfonyl group which may be substituentwith one or more groups selected from the substituent group A, anarylsulfonyl group which may be substituted with one or more groupsselected from the substituent group A, a tetrahydrofuranyl group, atetrahydropyranyl group, or a silyl group which may be substituted withone or more groups selected from the substituent group A, morepreferably a compound in which each of R^(4a), R^(4b), and R^(4c) is ahydrogen atom, a C₁₋₆ alkyl group which may be substituted with one ormore groups selected from the substituent group A, or an acyl groupwhich may be substituted with one or more groups selected from thesubstituent group A, even more preferable a compound in which each ofR^(4a), R^(4b), and R^(4c) is a hydrogen atom or an acyl group, andparticularly preferably a compound in which each of R^(4a), R^(4b), andR^(4c) is a hydrogen atom.

The compound represented by Formula (1) is preferably a compound inwhich R² and R³ are bonded to each other and represent a grouprepresented by formula (4).*—O—X¹—O—*  (4)

In the formula, each of X¹ and * has the same definition as describedabove.)

The compound represented by Formula (1) is preferably a compound inwhich R⁵ is an aryl group which may be substituted with one or moregroups selected from the substituent group A, more preferably a compoundin which R⁵ is a phenyl group which may be substituted with one or moregroups selected from the substituent group A, and even more preferably acompound in which R⁵ is a phenyl group which may be substituted with oneor more groups selected from the substituent group B.

The manufacturing method of the present invention is preferably amanufacturing method using a compound in which each of R^(1a) and R^(1b)is a carboxy protective group.

The carboxy protective group represented by R^(1a) and R^(1b) ispreferably a C₁₋₆ alkyl group which may be substituted with one or moregroups selected from the substituent group A, a C₂₋₆ alkenyl group whichmay be substituted with one or more groups selected from the substituentgroup A, an aryl group which may be substituted with one or more groupsselected from the substituent group A, an ar-C₁₋₆ alkyl group which maybe substituted with one or more groups selected from the substituentgroup A, a C₁₋₆ alkoxy C₁₋₆ alkyl group which may be substituted withone or more groups selected from the substituent group A, or a silylgroup which may be substituted with one or more groups selected from thesubstituent group A, more preferably a C₁₋₆ alkyl group which may besubstituted with one or more groups selected from the substituent groupA, even more preferably a C₁₋₆ alkyl group, and particularly preferablya C₁₋₃ alkyl group.

The manufacturing method of the present invention is preferably amanufacturing method using a compound in which each of R^(4a), R^(4b),and R^(4c) is a hydrogen atom, a C₁₋₆ alkyl group which may besubstituted with one or more groups selected from the substituent groupA, a C₂₋₆ alkenyl group which may be substituted with one or more groupsselected from the substituent group A, an ar-C₁₋₆ alkyl group which maybe substituted with one or more groups selected from the substituentgroup A, a C₁₋₆ alkoxy C₁₋₆ alkyl group which may be substituted withone or more groups selected from the substituent group A, an acyl groupwhich may be substituted with one or more groups selected from thesubstituent group A, a C₁₋₆ alkoxycarbonyl group which may besubstituted with one or more groups selected from the substituent groupA, a C₁₋₆ alkylsulfonyl group which may be substituted with one or moregroups selected from the substituent group A, an arylsulfonyl groupwhich may be substituted with one or more groups selected from thesubstituent group A, a tetrahydrofuranyl group, a tetrahydropyranylgroup, or a silyl group which may be substituted with one or more groupsselected from the substituent group A, more preferably a manufacturingmethod using a compound in which each of R^(4a), R^(4b), and R^(4c) is ahydrogen atom, a C₁₋₆ alkyl group which may be substituted with one ormore groups selected from the substituent group A, or an acyl groupwhich may be substituted with one or more groups selected from thesubstituent group A, even more preferably a manufacturing method using acompound in which each of R^(4a), R^(4b), and R^(4c) is a hydrogen atomor an acyl group, and particularly preferably a manufacturing methodusing a compound in which each of R^(4a), R^(4b), and R^(4c) is ahydrogen atom.

The manufacturing method of the present invention is preferably amanufacturing method using a compound in which R⁵ is an aryl group whichmay be substituted with one or more groups selected from the substituentgroup A, more preferably a manufacturing method using a compound inwhich R⁵ is a phenyl group which may be substituted with one or moregroups selected from the substituent group A, and even more preferably amanufacturing method using a compound in which R⁵ is a phenyl groupwhich may be substituted with one or more groups selected from thesubstituent group B.

The manufacturing method of the present invention is preferably amanufacturing method using a compound in which R⁶ is a C₁₋₆ alkyl groupwhich may be substituted with one or more groups selected from thesubstituent group A, more preferably a manufacturing method using acompound in which R⁶ is a C₁₋₆ alkyl group which may be substituted withone or more groups selected from the substituent group B, even morepreferably a manufacturing method using a compound in which R⁶ is a C₁₋₆alkyl group, and still more preferably a manufacturing method using acompound in which R⁶ is C₁₋₃ alkyl group.

The manufacturing method of the present invention is preferably amanufacturing method using a compound in which R⁷ is a C₁₋₃ alkyl groupwhich may be substituted with one or more groups selected from thesubstituent group A, more preferably a manufacturing method using acompound in which R⁷ is a C₁₋₃ alkyl group which may be substituted withone or more groups selected from the substituent group B, and even morepreferably a manufacturing method using a compound in which R⁷ is aalkyl group.

The manufacturing method of the present invention is preferably amanufacturing method using a compound in which R⁸ is a C₁₋₃alkylsulfonyl group which may be substituted with one or more groupsselected from the substituent group A or an arylsulfonyl group which maybe substituted with one or more groups selected from the substituentgroup A, more preferably a manufacturing method using a compound inwhich R⁸ is a C₁₋₃ alkysulfonyl group which may be substituted with oneor more groups selected front the substituent group B or an arylsulfonylgroup which may be substituted with one or more groups selected from thesubstituent group B, and even more preferably a manufacturing methodusing a compound in which R⁸ is an arylsulfonyl group which may besubstituted with one or more groups selected from the substituent groupB.

The manufacturing method of the present invention is preferably amanufacturing method using a compound in which R⁹ is an acyl group whichmay be substituted with one or more groups selected from the substituentgroup A, more preferably a manufacturing method using a compound inwhich R⁹ is a C₂₋₆ alkanoyl group which may be substituted with one ormore groups selected from the substituent group B, and even morepreferably a manufacturing method using a compound in which R⁹ is a C₂₋₆alkanoyl group.

Next, the manufacturing method of the present invention will bedescribed.

Manufacturing Method 1

(In the formulae, each of R^(1a), R^(1b), R^(4a), R^(4b), R^(4c), R⁵,and R⁶ has the same definition as described above.)

(1-1)

As the compound represented by Formula (9), for example, dimethylmethoxymethylene malonate is known.

The compound represented by Formula (1c) can be manufactured by reactingthe compound represented by Formula (8) with the compound represented byFormula (9) in the presence of a base.

The solvent used in this reaction is not particularly limited as long asthe solvent does not affect the reaction. Examples of the solventinclude aliphatic hydrocarbons, halogenated hydrocarbons, ethers,esters, ketones, nitriles, amides, sulfoxides, and aromatichydrocarbons. These solvents may be used by being mixed together.

Examples of preferred solvents include ethers, esters, ketones,nitriles, and amides, and among these, ethers are more preferable.

The amount of the solvent used is not particularly limited. The amountof the solvent used may be 1 time to 50 times (v/w) as much as theamount of the compound represented by Formula (8), and preferably 1 timeto 15 times (v/w) as much as the amount of the compound.

Examples of the base used in the reaction include inorganic bases, andamong these, tert-butoxypotassium, sodium ethoxide, and sodium methoxideare preferable, and tert-butoxypotassium is more preferable.

The amount of the base used is 0.01 times to 5 times as much as theamount of the compound represented by (8) in terms of mole, preferably0.02 times to 2 times as much as the amount of the compound in terms ofmole, and more preferably 0.03 times to 1 time as much as the amount ofthe compound in terms of mole.

The amount of the compound represented by Formula (9) used is 1.0 timeto 2.0 times as much as the amount of the compound represented byFormula (8) in terms of mole, preferably 1.0 time to 1.5 times as muchas the compound in terms of mole, and more preferably 1.0 time to 1.2times as much as amount of the amount of the compound in terms of mole.

The reaction temperature may be −20° C. to 100° C., preferably −10° C.,to 80° C., and even more preferably −5° C. to 60° C.

The reaction time may be 5 minutes to 50 hours, preferably 5 minutes to24 hours, and even more preferably 5 minutes to 6 hours.

(1-2)

The compound represented by Formula (1d) can be manufactured bysubjecting the compound represented by Formula (1c) to a deprotectionreaction.

Examples of the deprotection reaction include the method described in W.Greene et al, Protective Groups in Organic Synthesis, 4^(th) edition,pp. 299-366, 2007, John Wiley & Sons, INC, and the like.

Specifically, examples of the deprotection reaction include ahydrogenation reaction using a catalyst, a hydrolysis reaction using anacid, and the like.

The solvent used in the hydrogenation reaction is not particularlylimited as long as the solvent does not affect the reaction. Examples ofthe solvent include aliphatic hydrocarbons, halogenated hydrocarbons,alcohols, ethers, esters, ketones, nitriles, amides, sulfoxides,aromatic hydrocarbons, ureas, and water. These solvents may be used bybeing mixed together.

Preferred examples of the solvent include alcohols, ethers, esters,ketones, nitriles, and amides. Among these, alcohols and esters are morepreferable.

The amount of the solvent used is not particularly limited. The amountof the solvent used may be 1 time to 50 times (v/w) as much as theamount of the compound represented by Formula (1c), and preferably 1time to 15 times (v/w) as much as the amount of the compound.

Examples of the catalyst used in this reaction include ruthenium,rhodium, palladium, platinum, and nickel catalysts. Among these, Raneynickel, palladium-carbon (Pd/C), rhodium-carbon (Rh/C), an Adam'scatalyst (PtO₂), and a Pearlman's catalyst (Pd(OH)₂) are preferable, andpalladium-carbon and a Pearlman's catalyst are more preferable.

The amount of the catalyst used is 0.001% to 10% of the amount of thecompound represented by Formula (1c), and preferably 0.01% to 0.2% ofthe amount of the compound, and more preferably 0.05% to 0.1% of theamount or the compound.

The reaction temperature may be −20° C. to 100° C., preferably −10° C.to 80° C., and more preferably −5° C. to 60° C.

The reaction time may be 5 minutes to 50 hours, preferably 5 minutes to24 hours, and more preferably 5 minutes to 6 hours.

The solvent used in the hydrolysis reaction is not particularly limitedas long as the solvent does not affect the reaction. Examples of thesolvent include halogenated hydrocarbons, alcohols, ethers, ketones,nitriles, amides, sulfoxides, and water. These solvents may be used bybeing mixed together.

Preferred examples of the solvent include alcohols, ethers, nitriles,and water, and among these, alcohols are more preferable.

The amount of the solvent used is not particularly limited. The amountof the solvent used may be 1 time to 50 times (v/w) as much as theamount of the compound represented by Formula (1c), and more preferably1 time to 15 times (v/w) as much as the amount of the compound.

Examples of the acid used in this reaction include inorganic acids andorganic acids. Among these, hydrochloric acid, sulfuric acid,trifluoroacetic acid, and p-toluenesulfonic acid are preferable.

The amount of the acid used is 0.001 times to 2 times as much as theamount of the compound represented by Formula (1c) in terms of mole,preferably 0.005 times to 1.5 times as much as the amount of thecompound in terms of mole, and more preferably 0.01 times to 1 time asmuch as the amount of the compound in terms of mole.

The reaction time may be 5 minutes to 50 hours, preferably 5 minutes to24 hours and more preferably 5 minutes to 6 hours.

By the method for protecting a 1,3-diol group of the compoundrepresented by Formula (8) with the group represented by Formula (19)

(in the formula, R⁵ has the definition as described above)

(in the formula, each of R^(1a), R^(1b), and * has the same definitionas described above), it is possible to manufacture the compoundrepresented by Formula (1c) without decomposing a protective group for a1,3-diol group represented by Formula (A)

(in the formula, each of R⁵ and * has the static definition as describedabove)

(in the formula, each of R^(1a), R^(1b), and R⁵ has the same definitionas described above).

The protective group for a diol group represented by Formula (19) isstable in a step of deprotecting the protective group for a diol grouprepresented by Formula (A) (for example, a hydrogenation reaction usinga catalyst and a hydrolysis reaction performed in the presence of anacid).

The use of the group represented by Formula (19) as a protective groupfor a diol group makes it possible to selectively protect and deprotectdiol groups even in a case where two or more diol groups are present ina molecule.

(1-3)

The compound represented by Formula (1a) can be manufactured by reactingthe compound represented by Formula (1d) with a sulfur-containingcompound in the presence of a base and subjecting the resulting compoundto an oxidation reaction if necessary.

The solvent used is this reaction is not particularly limited as long asthe solvent does not affect the reaction. Examples of the solventinclude aliphatic hydrocarbons, halogenated hydrocarbons, ethers,nitriles and aromatic hydrocarbons. These solvents may be used by beingmixed together.

Preferred examples of the solvent include halogenated hydrocarbons,nitriles, and aromatic hydrocarbons, and among these, halogenatedhydrocarbons are more preferable.

The amount of the solvent used is not particularly limited. The amountof the solvent used may be 1 time to 50 times (v/w) as much as theamount of the compound represented by Formula (1c), and preferably 1time to 15 times (v/w) as much as the amount of the compound.

Examples of the base used in this reaction include organic bases, andamong these, triethylamine and diisopropylamine are preferable.

The amount of the base used is 0.8 times to 5 times as much as theamount of the compound represented by Formula (1d) in terms of mole,preferably 1 time to 3 times as much as the amount of the compound interms of mole, and more preferably 1.2 times to 2 times as much as theamount of the compound in terms of mole.

Examples of the sulfur-containing compound used in this reaction includesulfur dichloride, thionyl chloride, sulfuryl chloride, and sulfurtrioxide, and among these, thionyl chloride is preferable.

The amount of the sulfur-containing compound used is 0.8 times to 5times as much as the amount of the compound represented by Formula (1d)in terms of mole, preferably 0.9 times to 3 times as much as the amountof the compound in terms of mole, and more preferably 1 time to 2 timesas much as the amount of the compound in terms of mole.

The reaction temperature may be −20° C. to 100° C., preferably −15° C.to 70° C., and even more preferably −10° C. to 40° C.

The reaction time may be 5 minutes to 50 hours, preferably 5 minutes to24 hours, and even more preferably 5 minutes to 6 hours.

In a case where sulfur dichloride and thionyl chloride are used as thesulfur-containing compound, it is preferable to cause an oxidationreaction.

The solvent used in the oxidation reaction is not particularly limitedas long as the solvent does not affect the reaction. Examples of thesolvent include aliphatic hydrocarbons, halogenated hydrocarbons,ethers, nitriles, and aromatic hydrocarbons. These solvents may be usedby being mixed together.

Preferred examples of the solvent include halogenated hydrocarbons,nitriles, and aromatic hydrocarbons, and among these, halogenatedhydrocarbons and nitriles are more preferable.

The oxidant used in the oxidation reaction is not particularly limited.The oxidant is preferably potassium permanganate, ruthenium tetroxide,ruthenium (III) chloride-sodium periodate, or the like.

The amount of the oxidant used is 0.005 times to 0.2 times as much asthe amount of the compound represented by Formula (1d) in terms of mole,preferably 0.01 times to 0.1 times as much as the amount of the compoundin terms of mole, and more preferably 0.02 times to 0.05 times as muchas the amount of the compound in terms of mole.

The reaction temperature may be −20° C. to 100° C., preferably −10° C.to 80° C., and more preferably −5° C. to 60° C.

The reaction time may be 5 minutes to 50 hours, preferably 5 minutes to24 hours, and more preferably 5 minutes to 6 hours.

(1-4)

As the compound represented by Formula (7), for example,(2R,4S)-2-(hydroxymethyl)tetrahydrothiophene-3,4-diol is known.

The compound represented by Formula (1b) can be manufactured by reactingthe compound represented by Formula (1a) with the compound representedby Formula (7) in the presence of a base.

The solvent used in this reaction is not particularly limited as long asthe solvent does not affect the reaction. Examples of the solventinclude aliphatic hydrocarbons, halogenated hydrocarbons, alcohols,ethers, esters, ketones, nitriles, amides, sulfoxides, aromatichydrocarbons, ureas, and water. These solvents may be used by beingmixed together.

Preferred examples of the solvent include alcohols, ethers, ketones,nitriles, and sulfoxides, and among these, ketones are more preferable.

The amount of the solvent used is not particularly limited. The amountof the solvent used may be 1 time to 50 times (v/w) as much as theamount of the compound represented by Formula (1a), and preferably 1time to 15 times (v/w) as much as the amount of the compound.

Examples of the base used in this reaction include inorganic bases andorganic bases. Among these, sodium hydrogen carbonate, potassiumcarbonate, pyridine, 2,6-lutidine, and 4-dimethylaminopyridine arepreferable, and 2,6-lutidine is more preferable.

The amount of the base used is 0.01 times to 5 times as much as theamount of the compound represented by Formula (1a) in terms of mole,preferably 0.02 times to 2 times as much as the amount of the compoundin terms of mole, and more preferably 0.03 times to 1 time as much asthe amount of the compound in terms of mole.

The amount of the compound represented by Formula (7) used is 0.5 timesto 2 times as much as the amount of the compound represented by Formula(1a) in terms of mole, preferably 0.7 times to 1.2 times as much as theamount of the compound in terms of mole, and more preferably 0.8 to 1.1times as much as the amount of the compound in terms of mole.

The reaction temperature may be 0° C. to 150° C., preferably 10° C. to100° C., and more preferably 25° C. to 80° C.

The reaction time may be 5 minutes to 72 hours, preferably 30 minutes to50 hours, and more preferably 1 hour to 24 hours.

The compound represented by Formula (1b) contains isomers (atrans-isomer (1b-1) and a cis-isomer (1b-2).

The inventors of the present invention found that the compoundrepresented by Formula (1b-2) can be converted into the compoundrepresented by Formula (1b-1) through heating. Therefore, these isomersmay be used in the next reaction after being isolated, but it ispreferable to use these isomers as they are in the next reaction withoutisolating them.

(1-5)

Salacinol can be manufactured by subjecting the compound represented byFormula (1b) to a deprotection reaction in the presence of a base.

The solvent used in this reaction is not particularly limited as long asthe solvent does not affect the reaction. Examples of the solventinclude aliphatic hydrocarbons, halogenated hydrocarbons, alcohols,ethers, esters, ketones, nitriles, amides, sulfoxides, aromatichydrocarbons, ureas, and water. These solvents may be used by beingmixed together.

Preferred examples of the solvent include alcohols, ethers, esters,ketones, nitriles, and water, and among these, alcohols, ethers, esters,and water are more preferable.

The amount of the solvent used is not particularly limited. The amountof the solvent used may be 1 time to 50 times (v/w) as much as theamount of the compound represented by Formula (1b), and preferably 1time to 15 times (v/w) as much as the amount of the compound.

Examples of the base used in this reaction include inorganic bases andorganic bases. Among these, sodium hydrogen carbonate, sodium carbonate,potassium carbonate, sodium methoxide, propylamine, diethylamine,dibutylamine, triethylamine, diisopropylethylamine, pyridine,2,6-lutidine, 4-dimethylaminopyridine, tetraethylammonium hydroxide,diazabicycloundecene, diazabicyclononene, guanidine, and morpholine arepreferable, and sodium hydrogen carbonate, potassium carbonate, sodiummethoxide, propylamine, diethylamine, dibutylamine, triethylamine,diisopropylethylamine, pyridine, and morpholine are more preferable.

The amount of the base used is 0.1 times to 5 times as much as theamount of the compound represented by Formula (1b) in terms of mole,preferably 0.5 times to 2 times as much as the amount of the compound interms of mole, and more preferably 0.8 times to 1.5 times as much as theamount of the compound in terms of mole.

The reaction temperature may be 0° C. to 150° C., preferably 10° C. to100° C., and more preferably 25° C. to 80° C.

The reaction time may be 5 minutes to 72 hours, preferably 30 minutes to50 hours, and more preferably 1 hour to 24 hours.

The protective group for a diol group represented by Formula (19) iseasily deprotected by a base. In contrast, a methylene group, anisopropylidene group (acetonide), a benzylidene group, and the like thatare widely used as protective groups for a diol group are not easilydeprotected by a base.

(In the formula, each of R^(1a), R^(1b), and * has the same definitionas described above.)

The use of the group represented by Formula (19) as a protective groupfor a dial group makes it possible to selectively protect and deprotectdiol groups even in a case where two or more diol groups are present ina molecule.

In a case where the reaction is performed using the compound representedby Formula (1b-2), an isomer of salacinol is generated in some cases.

In this case, it is preferable that the isomer of salacinol is convertedinto salacinol by being subjected to a heating treatment as it iswithout being isolated.

Manufacturing Method 2

(In the formulae, each of R^(4ba), R⁷, R⁸, R⁹, L¹, and L² has the samedefinition as described above.)

(2-1)

As the compound represented by Formula (13), for example,(2R,3S,4S)-2-(hydroxymethyl)-5-methoxytetrahydrofuran-3,4-diol is known.The compound represented by Formula (13) may be prepared in a system.

As the compound represented by Formula (14), for example,p-toluenesulfonyl chloride is known.

The compound represented by Formula (15) can be manufactured by reactingthe compound represented by Formula (13) with the compound representedby Formula (14) in the presence of a base.

The solvent used in this reaction is not particularly limited as long asthe solvent does not affect the reaction. Examples of the solventinclude aliphatic hydrocarbons, halogenated hydrocarbons, ethers,esters, ketones, nitriles, amides, sulfoxides, aromatic hydrocarbons,ureas, and water. These solvents may be used by being mixed together.

Preferred examples of the solvent include ethers, esters, ketones,nitriles, and amides, and among these, nitriles are more preferable.

The amount of the solvent used is not particularly limited. The amountof the solvent used may be 1 time to 50 times (v/w) as much as theamount of the compound represented by Formula (13), and preferably 1time to 15 times (v/w) as much as the amount of the compound.

Examples of the base used in this reaction include organic bases. Amongthese, triethylamine, diisopropylethylamine, pyridine,4-dimethylaminopyridine, and N-methylimidazole are preferable.

The amount of the base used is 2.7 times to 10 times as much as theamount of the compound represented by Formula (13) in terms of mole,preferably 2.8 times to 6 times as much as the amount of the compound interms of mole, and more preferably 2.9 times to 4 times as much as theamount of the compound in terms of mole.

The amount of the compound represented by Formula (14) used is 2.7 timesto 10 times as much as the amount of the compound represented by Formula(13) in terms of mole, preferably 3 times to 6 times as much as theamount of the compound in terms of mole, and more preferably 3 times to4 times as much as the amount of the compound in terms of mole.

The reaction temperature may be −10° C. to 60° C., preferably 0° C. to50° C., and more preferably 10° C. to 40° C.

The reaction time may be 30 minutes to 24 hours, preferably 1 hour to 12hours, and more preferably 1.5 hours to 8 hours.

(2-2)

As the compound represented by Formula (16), for example, S-potassiumthioacetate is known.

The compound represented by Formula (17) can be manufactured by reactingthe compound represented by Formula (15) with the compound representedby Formula (16).

The solvent used in this reaction is not particularly limited as long asthe solvent does not affect the reaction. Examples of the solventinclude aliphatic hydrocarbons, halogenated hydrocarbons, ethers,esters, ketones, nitriles, amides, sulfoxides, aromatic hydrocarbons,ureas, and water. These solvents may be used by being mixed together.

Preferred examples of the solvent include ethers, esters, ketones,nitriles, and amides, and among these, amides are more preferable.

The amount of the solvent used is not particularly limited. The amountof the solvent used may be 1 time to 50 times (v/s) as much as theamount of the compound represented by Formula (15), and preferably 1time to 15 times (v/w) as much as the amount of the compound.

The amount of the compound represented by Formula (16) used is 0.8 timesto 5 times as much as the amount of the compound represented by Formula(15) in terms of mole, preferably 0.9 times to 4 times as much as theamount of the compound in terms of mole, and more preferably 1 time to 3times as much as the amount of the compound in terms of mole.

The reaction temperature may be 10° C. to 200° C. preferably 20° C. to150° C., and more preferably 30° C. to 100° C.

The reaction times may be 30 minutes to 24 hours, preferably 1 hour to18 hours, and more preferably 1.5 hours to 12 hours.

(2-3)

The compound represented by Formula (18) can be manufactured by reactingthe compound represented by Formula (17) with a base.

The solvent used in this reaction is not particularly limited as long asthe solvent does not affect the reaction. Examples of the solventinclude aliphatic hydrocarbons, halogenated hydrocarbons, alcohols,ethers, esters, ketones, nitriles, amides, sulfoxides, aromatichydrocarbons, ureas, and water. These solvents may be used by beingmixed together.

Preferred examples of the solvent include alcohols, ethers, esters,ketones, nitriles, amides, and sulfoxides, and among these, alcohols aremore preferable.

The amount of the solvent used is not particularly limited. The amountof the solvent used may be 1 time to 50 times (v/w) as much as theamount of the compound represented by Formula (17), and preferably 1time to 15 times (v/w) as much as the amount of the compound.

Examples of the base used in this reaction include inorganic bases andorganic bases. Among these, potassium carbonate, tert-butoxypotassium,triethylamine, and pyridine are preferable.

The amount of the base used is 0.9 times to 5 times as much as theamount of the compound represented by Formula (17) in terms of mole,preferably 0.95 times to 3 times as much as the amount of the compoundin terms of mole, and more preferably 1 time to 2 times as much as theamount of the compound in terms of mole.

The reaction temperature may be 10° C. to 200° C., preferably 20° C. to250° C., and more preferably 30° C. to 100° C.

The reaction time may be 30 minutes to 12 hours, preferably 1 hour to 8hours, and more preferably 1.5 hours to 4 hours.

The compound represented by Formula (18) may be used in the nextreaction after being isolated. However, it is preferably to use thecompound as it is in the next reaction without isolating it.

(2-4)

The compound represented by Formula (10) can be manufactured bysubjecting the compound represented by Formula (18) to a deprotectionreaction.

Examples of the deprotection reaction include the method described in W.Greene et al, Protective Groups in Organic Synthesis, 4^(th) edition,pp. 272-279, 2007, John Wiley & Sons, INC., and the like.

Specifically, examples of the deprotection reaction include a hydrolysisreaction using a base, and the like.

The solvent used in the hydrolysis reaction is not particularly limitedas long as the solvent does not affect the reaction. Examples of thesolvent include aliphatic hydrocarbons, halogenated hydrocarbons,ethers, esters, ketones, nitriles, amides, sulfoxides, aromatichydrocarbons, ureas, and water. These solvents may be used by beingmixed together.

Preferred examples of the solvent include alcohols, ethers, esters,ketones, nitriles, amides, sulfoxides, and water, and among these, mixedsolvents of alcohols and water are more preferable.

The amount of the solvent used is not particularly limited. The amountof the solvent used may be 1 time to 50 times (v/w) as much as theamount of the compound represented by Formula (18), and preferably 1time to 15 times (v/w) as much as the amount of the compound.

Examples of the base used in the hydrolysis reaction include inorganicbases. Among these, sodium hydroxide and potassium hydroxide arepreferable.

The amount of the base used is 1 time to 20 times as much as the amountof the compound represented by Formula (18) in terms of mole, preferably1 time to 15 times as much as the amount of the compound in terms ofmole, and more preferably 1 time to 10 times as much as the amount ofthe compound in terms of mole.

The reaction temperature may be 10° C. to 200° C., preferably 20° C. to150° C., and more preferably 30° C. to 100° C.

The reaction time may be 10 minutes to 12 hours, preferably 20 minutesto 8 hours, and more preferably 30 minutes to 4 hours.

(2-5)

As the compound represented by Formula (11), for example, p-toluoylchloride is known.

The compound represented by Formula (12) can be manufactured by reactingthe compound represented by Formula (10) with the compound representedby Formula (11) in the presence of a base.

The solvent used in this reaction is not particularly limited as long asthe solvent does not affect the reaction. Examples of the solventinclude aliphatic hydrocarbons, halogenated hydrocarbons, ethers,esters, ketones, nitriles, amides, sulfoxides, aromatic hydrocarbons,ureas, and water. These solvents may be used by being mixed together.

Preferred examples of the solvent include ethers, esters, ketones,nitriles, amides, and aromatic hydrocarbons, and among these, esters andaromatic hydrocarbons are more preferable.

The amount of the solvent used is not particularly limited. The amountof the solvent used may be 1 time to 50 times (v/w) as much as theamount of the compound represented by Formula (10), and preferably 1time to 15 times (v/w) as much as the amount of the compound.

Examples of the base used in this reaction include inorganic bases andorganic bases. Among these, sodium hydroxide, potassium carbonate,sodium methoxide, triethylamine, and pyridine are preferable.

The amount of the base used is 1 time to 10 times as much as the amountof the compound represented by Formula (10) in terms of mole, preferably1 time to 5 times as much as the amount of the compound in terms ofmole, and more preferably 1 time to 3 times as much as the amount of ascompound in terms of mole.

The amount of the compound represented by Formula (11) used is 0.9 timesto 5 times as much as the amount of the compound represented by Formula(10) in terms of mole, preferably 0.95 times to 3 times as much as theamount of the compound in terms of mole, and more preferably 1 time to 2times as much as the amount of the compound in terms of mole.

The reaction temperature may be −10° C. to 60° C., preferably 0° C. to50° C., and more preferably 10° C. to 40° C.

The reaction time may be 30 minutes to 12 hours, preferably 1 hour to 8hours, and more preferably 1.5 hours to 4 hours.

(2-6)

The compound represented by Formula (7a) can be manufactured by reactingthe compound represented by Formula (12) with an acid and thensubjecting the resulting compound to a reduction reaction.

The solvent used in this reaction is not particularly limited as long asthe solvent does not affect the reaction. Examples of the solventinclude aliphatic hydrocarbons, halogenated hydrocarbons, alcohol,ethers, esters, ketones, nitriles, amides, sulfoxides, aromatichydrocarbons, ureas, and water. These solvents may be used by beingmixed together.

Preferred examples of the solvent include alcohol, ether, and water, andamong these, mixed solvents of ethers and water are more preferable.

The amount of the solvent used is not particularly limited. The amountof the solvent used may be 1 time to 50 times (v/w) as much as theamount of the compound represented by Formula (12), and preferably 1time to 15 times (v/w) as much as the amount of the compound.

Examples of the acid used in this reaction include inorganic acids andorganic acids. Among these, hydrochloric acid, sulfuric acid,p-toluenesulfonic acid, and camphorsulfonic acid are preferable.

The amount of the acid used is 1 time to 5 times as much as the amountof the compound represented by Formula (12) in term of mole, preferably1 time to 3 times as much as the amount of the compound in terms ofmole, and more preferably 1 time to 2 times as much as the amount of thecompound in terms of mole.

Examples of the reductone used in this reaction include complex hydridecompounds such as lithium aluminum hydride, sodiumtriacetoxyborohydride, sodium cyanoborohydride, and sodium borohydride;borane; sodium; and sodium amalgam. It is also possible to useelectrolytic reduction using copper or platinum as a cathode; contactreduction using Raney nickel, platinum oxide, or palladium black;reduction using “zinc-acid”; and the like.

Preferred examples of the reductone include sodium borohydride. A solidof sodium borohydride or a solution of sodium borohydride can be used.

The amount of the reductone used is 1 time to 5 times as much as theamount of the compound represented by Formula (12) in terms of mole,preferably 1 time to 4 times as much as the amount of the compound interms of mole, and more preferably 1 time to 3 times as much as theamount of the compound in terms of mole.

The temperature of the reaction with an acid may be 0° C. to 150° C.,preferably 10° C. to 100° C., and more preferably 20° C. to 80° C.

The time of the reaction with an acid may be 10 minutes to 12 hours,preferably 20 minutes to 8 hours, and more preferably 30 minutes to 4hours.

The temperature of the reduction reaction may be −10° C. to 60° C.,preferably 0° C. to 50° C., and more preferably 10° C. to 40° C.

The time of the reduction reaction may be 10 minutes to 12 hours,preferable 20 minutes to 8 hours, and more preferably 30 minutes to 4hours.

(2-7)

The compound represented by Formula (7b) can be manufactured bysubjecting the compound represented by Formula (7a) to a deprotectionreaction.

Examples of the deprotection reaction include the method described in W.Greene et al. Protective Groups in Organic Synthesis, 4^(th) edition,pp. 255-265, 2007, John Wiley & Sons, INC., and the like.

Specifically, examples of the deprotection reaction include a hydrolysisreaction using a base.

The solvent used in the hydrolysis reaction is not particularly limitedas long as the solvent does not affect the reaction. Examples of thesolvent include aliphatic hydrocarbons, halogenated hydrocarbons,alcohols, ethers, esters, ketones, nitriles, amides, sulfoxides,aromatic hydrocarbons, ureas, and water. These solvents may be used bybeing mixed together.

Preferred examples of the solvent include alcohols, ethers, and water,and among these, alcohols are more preferable.

The amount of the solvent used is not particularly limited. The amountof the solvent used may be 1 time to 50 times (v/w) as much as theamount of the compound represented by Formula (7a), and preferably 1time to 15 times (v/w) as much as the amount of the compound.

Examples of the base used in the hydrolysis reaction include inorganicbases and organic bases. Among these, sodium hydroxide, potassiumcarbonate, and sodium methoxide are preferable.

The amount of the base used is 0.001 times to 3 times as much as theamount of the compound represented by Formula (7a) in terms of mole,preferably 0.005 times to 1 time as much as the amount of the compoundin terms of mole, and more preferably 0.01 times to 0.5 times as much asthe amount of the compound in terms of mole.

The reaction temperature may be −10° C. to 80° C., preferably 0° C. to60° C.; and more preferably 10° C. to 40° C.

The reaction time may be 10 minutes to 24 hours, preferably 20 minutesto 12 hours, and more preferably 30 minutes to 8 hours.

Manufacturing Method 3

(In the formula, each of R^(1a), R^(1b), and * has the same definitionas described above.)

A 1,2-diol group or a 1,3-diol group is reacted with the grouprepresented by Formula (19) in the presence of a base, and in this way,the diol group can be protected.

Specifically, the compound represented by Formula (21) is manufacturedby reacting the compound represented by Formula (20) with the compoundrepresented by Formula (9) in the presence of a base, and in this way, adiol group can be protected. That is, the compound represented byFormula (9) is useful as a protective agent for a 1,2-diol group or a1,3-diol group.

(In the formula, each of R^(1a), R^(1b), R⁶, and Y¹ has the samedefinition as described above.)

The solvent used in this reaction is not particularly limited as long asthe solvent does not affect the reaction. Examples of the solventinclude aliphatic hydrocarbons, halogenated hydrocarbons, ethers,esters, ketones, nitriles, amides, sulfoxides, and aromatichydrocarbons. These solvents may be used by being mixed together.

Preferred examples of the solvent include ethers, esters, ketones,nitriles, and amides, and among these, ethers are more preferable.

The amount of the solvent used is not particularly limited. The amountof the solvent used may be 1 time to 50 times (v/w) as much as theamount of the compound represented by Formula (20), and preferably 1time to 15 times (v/w) as much as the amount of the compound.

The compound represented by Formula (20) that is used in this reactionis not particularly limited as long as the compound has a diol group ina molecule.

Specifically, the compound represented by Formula (20) can berepresented by, for example, Formula (20a).

(In the formula, m is 0 or 1; R^(A), R^(B), and R^(C) are the same as ordifferent from each other and each represent a hydrogen atom, a halogenatom, a cyano group, a nitro group, a protected amino group, a protectedhydroxy group, a protected carboxy group, a C₁₋₆ alkyl group which maybe substituted with one or more groups selected from the substituentgroup A, a C₁₋₆ alkenyl group which may be substituted with one or moregroups selected from the substituent group A, an aryl group which may besubstituted with one or more groups selected from the substituent groupA, a C₁₋₆ alkoxy group which may be substituted with one or more groupsselected from the substituent group A, an acyl group which may besubstituted with one or more groups selected from the substituent groupA, a C₁₋₆ alkylamino group which may be substituted with one or moregroups selected front the substituent group A, a di(C₁₋₆ alkyl)aminogroup which may be substituted with one or more groups selected from thesubstituent group A, a C₁₋₆ alkylthio group which may be substitutedwith one or more groups selected from the substituent group A, a C₁₋₆alkylsulfonyl group which may be substituted with one or more groupsselected from the substituent group A, an arylsulfonyl group which maybe substituted with one or more groups selected from the substituentgroup A, or a heterocyclic group which may be substituted with one ormore groups selected from the substituent group A; or R^(A) and R^(B)may be bonded to each other together with carbon atoms to which R^(A)and R^(B) are bonded and form a C₃₋₈ cycloalkyl ring which may besubstituted with one or more groups selected from the substituent groupA or a non-aromatic heterocyclic ring which may be substituted with oneor more groups selected from the substituent group A.)

The compound represented by Formula (20) is preferably a compound itswhich R^(A), R^(B), and R^(C) are the same as or different from eachother and each represent a hydrogen atom, a halogen atom, a protectedamino group, a protected hydroxy group, a protected carboxy group, aC₁₋₆ alkyl group which may be substituted with one or more groupsselected from the substituent group A, an aryl group which may besubstituted with one or more groups selected from the substituted groupA, or a heterocyclic group which may be substituted with one or moregroups selected from the substituent group A.

The compound represented by Formula (20) is preferably a compound inwhich R^(A) and R^(B) are bonded to each other together with carbonatoms to which R^(A) and R^(B) are bonded and each represent a C₅₋₈cycloalkyl ring which may be substituted with one or more groupsselected from the substituent group A or a non-aromatic heterocyclicring which may be substituted with one or more groups selected from thesubstituent group A.

The compound represented by Formula (9) is preferably the followingcompound.

The compound represented by Formula (9) is preferably a compound inwhich R^(1a) and R^(1b) each represent a carboxy protective group.

The carboxy protective group represented by R^(1a) and R^(1b) ispreferably a C₁₋₆ alkyl group which may be substituted with one or moregroups selected from the substituent group A, a C₁₋₆ alkenyl group whichmay be substituted with one or more groups selected from the substituentgroup A, an aryl group which may be substituted with one or more groupsselected from the substituent group A, an ar-C₁₋₆ alkyl group which maybe substituted with one or more groups selected from the substituentgroup A, a C₁₋₆ alkoxy alkyl group which may be substituted with one ormore groups selected from the substituent group A, or a silyl groupwhich may be substituted with one or more groups selected from thesubstituent group A, more preferably a C₁₋₆ alkyl group which may besubstituted with one or more groups selected from the substituent groupA, even more preferably a C₁₋₆ alkyl group, and particularly preferablya C₁₋₃ alkyl group.

The C₁₋₆ alkyl group represented by R⁶ may be substituted with one ormore groups selected from the substituent group A.

The compound represented by Formula (9) is preferably a compound inwhich R⁶ is a C₁₋₆ alkyl group which may be substituted with one or moregroups selected from the substituent group B, more preferably a compoundin which R⁶ is a C₁₋₆ alkyl group, and even more preferably a compoundin which R⁶ is a C₁₋₃ alkyl group.

The amount of the compound represented by Formula (9) used is 1.0 timeto 2.0 times as much as the amount of the compound represented byFormula (20) in terms of mole, preferably 1.0 time to 1.5 times as muchas the amount of the compound in terms of mole, and more preferably 1.0time to 1.2 times as much as the amount of the compound in terms ofmole.

Examples of the base used in this reaction include inorganic bases.Among these, tert-butoxypotassium, sodium ethoxide, and sodium methoxideare preferable, and tert-butoxypotassium is more preferable.

The amount of the base used is 0.01 times to 5 times as much as theamount of the compound represented by Formula (20) in terms of mole,preferably 0.02 times to 2 times as much as the amount of the compoundin terms of mole, and more preferably 0.03 times to 1 time as much asthe amount of the compound in terms of mole.

The reaction temperature may be −20° C. to 100° C., preferably −10° C.to 80° C., and more preferably −5° C., to 60° C.

The reaction time may be 5 minutes to 50 hours, preferably 5 minutes to24 hours, and more preferably 5 minutes to 6 hours.

Manufacturing Method 4

1,2-Diol group or 1,3-diol group protected with

(In the formula, each of R^(1a), R^(1b), * has the same definition asdescribed above.)

By reacting the 1,2-diol group or the 1,3-diol group, which is protectedwith the group represented by Formula (19), with a base, the protecteddiol group can be deprotected.

Specifically, by manufacturing the compound represented by Formula (20)by reacting the compound represented by Formula (21) with a base, theprotected diol group can be deprotected.

(In the formula, each of R^(1a), R^(1b), and Y¹ has the same definitionas described above.)

The solvent used in this reaction is not particularly limited as long asthe solvent does not affect the reaction. Examples of the solventinclude aliphatic hydrocarbons, halogenated hydrocarbons, alcohols,ethers, esters, ketones, nitriles, amides, sulfoxides, aromatichydrocarbons, ureas, and water. These solvents may be used by beingmixed together.

Preferred examples of the solvent include alcohols, ethers, esters,ketones, nitriles, and water, and among these, alcohols, ethers, esters,and water are more preferable.

The amount of the solvent used is not particularly limited. The amountof the solvent used may be 1 time to 50 times (v/w) as much as theamount of the compound represented by Formula (21), and preferably 1time to 15 times (v/w) as much as the amount of the compound.

Examples of the base used in this reaction include inorganic bases andorganic bases. Among these, sodium hydrogen carbonate, sodium carbonate,potassium carbonate, sodium methoxide, propylamine, diethylamide,dibutylamine, triethylamine, diisopropylethylamine, pyridine,2,6-lutidine, 4-dimethylaminopyridine, tetraethylammonium hydroxide,diazabicycloundecene, diazabicyclononene, guanidine, and morpholine arepreferable, and sodium hydrogen carbonate, potassium carbonate, sodiummethoxide, propylamine, diethylamine, dibutylamine, triethylamine,diisopropylethylamine, pyridine, and morpholine are more preferable.

The amount of the base used is 0.1 times to 5 times as much as theamount of the compound represented by Formula (21) in terms of mole,preferably 0.5 times to 2 times as much as the amount of the compound interms of mole, and more preferably 0.8 times to 1.5 times as much as theamount of the compound in terms of mole.

The reaction temperature may be 0° C. to 150° C., preferably 10° C. to100° C., and even more preferably 25° C. to 80° C.

The reaction time may be 5 minutes to 72 hours, preferably 30 minutes to50 hours, and more preferably 1 hour to 24 hours.

The protective group for a diol group represented by formula (19) iseasily deprotected by a base. In contrast, the protective group for adiol group represented by Formula (19) is not deprotected in a step (forexample, a hydrogenation reaction using a catalyst or a hydrolysisreaction performed in the presence of an acid) of deprotecting abenzylidene group widely used as a protective group for a diol group.

(In the formula, each of R^(1a), R^(1b), and * has the same definitionas described above.)

The use of the group represented by Formula (19) as a protective groupfor a diol group makes it possible to selectively protect and deprotectdiol groups even in a case where two or more diol group are present in amolecule.

The compounds obtained by the aforementioned manufacturing methods canbe isolated and purified by a general method such as extraction,crystallization, distillation, or column chromatography. Furthermore,the compounds obtained by the aforementioned manufacturing methods maybe used as they are in the next reaction without being isolated.

In a case where crystalline polymorphs, hydrates, or solvates arepresent in the compounds obtained by the aforementioned manufacturingmethods, all of the crystal forms, hydrates, and solvates can be used inthe present invention.

Next, the present invention will be described based on referenceexamples and examples, but the present invention is not limited thereto.

EXAMPLES

Unless otherwise specified, as a carrier for silica gel columnchromatography, an FR-260 HI-FLAS™ COLUMN manufactured by YAMAZENCORPORATION and WAKOGEL C-200 manufactured by Wako Pure ChemicalIndustries, Ltd. was used.

A mixing ratio in an eluant is volume ratio. For example, “hexane/ethylacetate=90/10 to 50/50” means an eluant of 90% hexane/10% ethyl acetateis finally changed to an eluant of 50% hexane/50% ethyl acetate.

An NMR spectrum was measured using tetramethylsilane is an internalstandard and using BRUKER AV 300 (Bruker Corporation) or JNM-AL400 model(JEOL Ltd.), and all of the δ values were expressed using ppm.

Each abbreviation in each example means the following.

-   Ac: acetyl-   Bn: benzyl-   Et: ethyl-   Me: methyl-   Ph: phenol-   PMB: 4-methoxybenzyl-   Tol: p-toluoyl-   Ts: 4-methylbenzenesulfonyl-   DMSO-D₆: deuterated dimethyl sulfoxide-   pyridine-D₅: deuterated pyridine-   HPLC: high performance liquid chromatography

Reference Example 1

2.00 g of 60% sodium hydride was added to 15 mL of aN,N-dimethylformamide solution containing 1.50 g of(2R,3S,4S)-2-(hydroxymethyl)tetrahydrothiphene-3,4-diol at 0° C., andthe resulting mixture was stirred for 1 hour at a temperature of equalto or lower than 5° C. Then, 4.50 mL of benzyl bromide was added theretoat 0° C., followed by stirring for 3 hours at 25° C. Ethyl acetate andwater were added to the reaction mixture. An organic layer was collectedby separation, washed with a saturated aqueous sodium chloride solution,and dried over anhydrous magnesium sulfate, and the solvent wasdistilled away under reduced pressure. The obtained residue was purifiedby column chromatography (hexane/ethyl acetate=95/5 to 86/14), therebyobtaining 2.31 g of(2R,3S,4S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)tetrahydrothiopheneas a colorless oily substance.

¹H-NMR (CDCl₃) δ values: 2.90 (1H, dd, J=4.8, 11.4 Hz), 3.04 (1H, dd,J=5.0, 11.4 Hz), 3.47-3.59 (2H, m), 3.69 (1H, t, J=7.8 Hz), 4.10-4.21(2H, m), 4.45-4.61 (6H, m), 7.25-7.35 (15H, m).

Reference Example 2

1.49 g of 60% sodium hydride was added to 10 mL of aN,N-dimethylformamide solution containing 1.12 g of(2R,3S,4S)-2-(hydroxymethyl)tetrahydrothiophene-3,4-diol at 0° C., andthe resulting mixture was stirred for 30 minutes at a temperature ofequal to or lower than 5° C. Then, 3.86 mL of 4-methoxybenzyl chloridewas added thereto at 0° C. followed by stirring for 6 hours at 25° C.Ethyl acetate and water were added to the reaction mixture. An organiclayer was collected by separation, washed with a saturated aqueoussodium chloride solution, and dried over anhydrous magnesium sulfate,and the solvent was distilled away under reduced pressure. The obtainedresidue was purified by column chromatography (hexane/ethyl acetate=95/5to 86/14), thereby obtaining 1.93 g of(2R,3S,4S)-3,4-bis((4-methoxybenzyl)oxy)-2-(((4-methoxybenzyl)oxy)methyl)tetrahydrothiopbene as a colorless oily substance.

¹H-NMR (CDCl₃) δ values: 2.86 (1H, dd, J=4.8, 11.4 Hz), 3.03 (1H, dd,J=5.2, 11.4 Hz), 3.42-3.52 (2H, m), 3.64 (1H, dd, J=7.2, 8.1 Hz),3.79-3.81 (9H, m), 4.03-4.16 (2H, m), 4.39-4.52 (6H, m), 6.84-6.87 (6H,m), 7.18-7.25 (6H, m).

Example 1

1.1 g of tert-butoxypotassium was added to 200 mL of a tetrahydrofuransolution containing 20.0 g of(4S,5R)-4-(hydroxymethyl)-2-phenyl-1,3-dioxan-5-ol and 18.2 g ofdimethyl methoxymethylone malonate at 25° C., and the resulting mixturewas stirred for 1 hour at 25° C. Toluene was added to the reactionmixture, tetrahydrofuran was distilled away under reduced pressure, andthen ethyl acetate and water were added thereto. An organic layer wascollected by separation, washed sequentially with water and then with asaturated aqueous sodium chloride solution, and dried over anhydrousmagnesium sulfate, and the solvent was distilled away under reducedpressure. The obtained residue was recrystallized from methanol therebyobtaining 21.3 g of dimethyl.2-((4aS,8aR)-6-phenyltetrahydro[1,3]dioxino[5,4-d][1,3]dioxin-2-yl)malonateas a white solid.

¹H-NMR (CDCl₃) δ values: 3.75-3.81 (11H, m), 4.23-4.31 (2H, m), 5.30(1H, d, J=7.8 Hz), 5.60 (1H, s), 7.35-7.39 (3H, m), 7.44-7.50 (2H, m).

Example 2

1.24 g of 20% palladium hydroxide/carbon was added to 70 mL of an ethylacetate solution containing 20.4 g of dimethyl2-((4aS,8aR)-6-phenyltetrahydro[1,3]dioxino[5,4-d][1,3]dioxin-2-yl)malonateat 25° C., and the resulting mixture was stirred for 4 hours in ahydrogen atmosphere (5 MPa). After insoluble matters were removed byfiltration, the solvent was distilled away under reduced pressure,thereby obtaining 15.7 g of dimethyl2-((4R,5S)-5-hydroxy-4-(hydroxymethyl)-1,3-dioxan-2-yl)malonate as acolorless oily substance.

¹-NMR (CDCl₃) δ values: 2.40 (1H, s), 2.70 (1H, s), 3.44-3.56 (2H, m),3.68 (1H, d, J=7.2 Hz), 3.76-3.85 (9H, m), 4.11-4.21 (1H, m), 5.15 (1H,d, J=7.2 Hz).

Example 3

112 mL of triethylamine was added to 800 mL of a methylene chloridesolution containing 53.0 g of dimethyl2-((4R,5S)-5-hydroxy-4-(hydroxymethyl)-1,3-dioxan-2-yl)malonate at atemperature of equal to or lower than −5° C., and then 500 mL of amethylene chloride solution containing 21.8 mL of thionyl chloride wasadded dropwise thereto at a temperature of equal to or lower than −5° C.The reaction mixture was stirred for 20 minutes at a temperature ofequal to or lower than 5° C., and then water was added thereto. Anorganic layer was collected by separation and washed sequentially with 1mol/L hydrochloric acid, water, and then a saturated aqueous sodiumhydrogen carbonate solution, and the solvent was distilled away underreduced pressure.

A mixed solution of 265 mL of methylene chloride containing the obtainedresidue and 265 mL of acetonitrile was added dropwise to 530 mL of watercontaining 150 g of sodium periodate and 1.25 g of a ruthenium (III)chloride n-hydrate at 0° C., followed by stirring for 20 minutes. Ethylacetate was added to the reaction mixture. An organic layer wascollected by separation, washed sequentially with water, a 10% aqueoussodium thiosulfate solution, and then a saturated aqueous sodiumchloride solution, and anhydrous magnesium sulfate and silica gel wereadded thereto, followed by stirring for 5 minutes. After insolublematters were removed by filtration, the solvent was distilled away underreduced pressure, and the obtained residue was recrystallized frommethanol and water, thereby obtaining 42.3 g of dimethyl2-((4aR,8aS)-2,2-dioxidotetrahydro[1,3]dioxino[5,4-d][1,3,2]dioxathiin-6-yl)malonateas a white solid.

¹H-NMR (CDCl₃) δ values: 3.70 (1H, d, J=7.8 Hz), 3.77 (3H, s), 3.78 (3H,s), 3.82 (1H, d, J=10.5 Hz), 4.01-4.11 (1H, m), 4.31 (1H, dd, J=5.0,10.5 Hz), 4.56 (1H, dd, J=5.0, 10.5 Hz), 4.54-4.75 (2H, m), 5.27 (1H, d,J=7.8 Hz).

Example 4

31 μL of 2,6-lutidine was added to 1.5 mL of an acetone solutioncontaining 500 mg of(2R,3S,4S)-2-(hydroxymethyl)tetrahydrothiophene-3,4-diol and 1.14 g ofdimethyl2-((4aR,8aS)-2,2-dioxidotetrahydro[1,3-]dioxino[5,4-d][1,3,2]dioxathiin-6-yl)malonateat 25° C., followed by stirring for 13 hours at 70° C. The reactionmixture was cooled to room temperature, acetone was added thereto, andsolids were collected by filtration, thereby obtaining 1.20 g of(4S,5S)-4-(((2R,3S,4S)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-ium-1-yl)methyl-2-(1,3-dimethoxy-1,3-dioxopropan-2-yl)-1,3-dioxan-5-yl sulfate asa white solid.

As a result of measuring ¹H-NMR and HPLC, it was confirmed that a ratioof trans/cis was 78/22.

¹H-NMR (DMSO-D₆) δ values: 3.56-3.63 (2H, m), 3.62-3.73 (8H, m),3.42-4.08 (6H, m), 4.14 (1H, dd, J=5.3, 10.2 Hz), 4.22-4.29 (2H, m),4.47-4.53 (1H, m), 5.21 (1H, d, J=7.5 Hz), 5.57 (2H, s), 6.13 (2H, m).

Example 5

756 μL of diethylamine was added to a mixed solution of 14.5 mL of waterand 14.5 mL of ethyl acetate containing 2.90 g of(4S,5S)-4-(((2R,3S,4S)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-ium-1-yl)methyl-2-(1,3-dimethoxy-1,3-dioxopropan-2-yl)-1,3-dioxan-5-yl sulfate(trans/cis=78/22) at 25° C., followed by stirring for 50 minutes at 25°C. An aqueous layer was collected by separation and washed with ethylacetate, and the solvent was distilled away under reduced pressure. Theobtained residue was recrystallized from methanol thereby obtaining 1.05g of(2S,3S)-4-(((2S,2R,3S,4S)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-ium-1-yl)-1,3-dihydroxybutan-2-ylsulfate (salacinol) as a white solid.

¹H-NMR (pyridine-D₅) δ values: 4.32-4.39 (3H, m), 4.51-4.66 (5H, m),4.75-4.82 (1H, m), 4.91-5.05 (1H, m), 5.09-5.14 (2H, m), 5.23-5.27 (1H,m).

220 μL of triethylamine was added to a mixed solution of 2.5 mL of waterand 2.5 mL of methanol containing 500 mg of(4S,5S)-4-(((2R,3S,4S)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-ium-1-yl)methyl-2-(1,3-dimethoxy-1,3-dioxopropan-2-yl)-1,3-dioxan-5-yl sulfate(trans/cis=78/22) at 25° C., followed by stirring for 5 hours at 25° C.Ethyl acetate was added to the reaction mixture. An aqueous layer wascollected by separation and washed with ethyl acetate, and the solventwas distilled away under reduced pressure.

As a result of measuring the obtained residue by HPLC, it was confirmedthat salacinol was generated, and the reaction rate was 97%.

(5-3)

220 μL of propylamine was added to a mixed solution of 2.5 mL of waterand 2.5 mL of toluene containing 500 mg of(4S,5S)-4-(((2R,3S,4S)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-ium-1-yl)methyl-2-(1,3-dimethoxy-1,3-dioxopropan-2-yl)-1,3-dioxan-5-yl sulfate(trans/cis=78/22) at 25° C., followed by stirring for 1 hour at 25° C.Toluene was added to the reaction mixture. An aqueous layer wascollected by separation, and the solvent was distilled away underreduced pressure.

As a result of measuring the obtained residue by HPLC, it was confirmedthat salacinol was generated, and the reaction rate was 96%.

(5-4)

212 μL of dibutylamine was added to a mixed solution of 2.5 mL of waterand 2.5 mL of toluene containing 500 mg of(4S,5S)-4-(((2R,3S,4S)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-ium-1-yl)methyl-2-(1,3-dimethoxy-1,3-dioxopropan-2-yl)-1,3-dioxan-5-yl sulfate(trans/cis=78/22) at 25° C., followed by stirring for 4 hours at 25° C.Toluene was added to the reaction mixture. An aqueous layer wascollected by separation, and the solvent was distilled away underreduced pressure.

As a result of measuring the obtained residue by HPLC, it was confirmedthat salacinol was generated, and the reaction rate was 85%.

(5-5)

10 mL of an aqueous solution containing 1 g of(4S,5S)-4-(((2R,3S,4S)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-ium-1-yl)methyl-2-(1,3-dimethoxy-1,3-dioxopropan-2-yl)-1,3-dioxan-5-yl sulfate(trans/cis=78/22) was stirred for 8 hours at 70° C., and then thesolvent was distilled away under reduced pressure. 203 μL of pyridineand 287 μL of aniline were added to a mixed solution of 5 mL of waterand 5 mL of methanol containing the obtained oily substance at 25° C.,followed by stirring for 13 hours at 50° C. Toluene was added to thereaction mixture. An aqueous layer was collected by separations andwashed with ethyl acetate, and the solvent was distilled away underreduced pressure.

The obtained residue was recrystallized from methanol, thereby obtaining485 mg of salacinol as a white solid.

Example 6

31 μL of 2,6-lutidine was added to 1.5 mL of acetone solution containing1.24 g of(2R,3S,4S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)tetrahydrothiophenand 1.01 g of dimethyl2-(4aR,8aS)-2,2-dioxidotetrahydro[1,3]dioxino[5,4-d][1,3,2]dioxathiin-6-yl)malonateat 25° C., followed by stirring for 24 hours at 70° C. The reactionmixture was cooled to room temperature, and the solvent was distilledaway under reduced pressure. The obtained residue was purified by columnchromatography (chloroform/methanol=99/1 to 95/5), thereby obtaining1.32 g of(4S,5S)-4-(((1S,2R,3S,4S)-3,4-(bis(benzyloxy)-2-((benzyloxy)methyl)tetrahydro-1H-thiophen-1-ium-1-yl)methyl)-2-(1,3-dimethoxy-1,3-dioxopropan-2-yl)-1,3-dioxan-5-ylsulfate as a colorless oily substance.

¹H-NMR (DMSO-D₆) δ values: 3.56-3.66 (7H, m), 3.72-3.76 (2H, m),3.88-4.16 (7H, m), 4.24-4.38 (2H, m), 4.51-4.64 (7H, m), 4.76-4.79 (1H,m), 5.17 (1H, d, J=7.2 Hz), 7.33-7.37 (15H, m).

Example 7

73 μL of diethylamine was added to 4.4 mL of a methanol solutioncontaining 440 mg of(4S,5S)-4-(((1S,2R,3S,4S)-3,4-(bis(benzyloxy)-2-((benzyloxy)methyl)tetrahydro-1H-thiophen-1-ium-1-yl)methyl)-2-(1,3-dimethoxy-1,3-dioxopropan-2-yl)-1,3-dioxan-5-ylsulfate at 25° C., followed by stirring for 1 hour at 25° C. The solventof the reaction mixture was distilled away under reduced pressure, andthe obtained residue was purified by column chromatography(chloroform/methanol=100/0 to 92/8), thereby obtaining 240 mg of(2S,3S)-4-((1R,2R,3S,4S)-3,4-(bis(benzyloxy)-2-((benzyloxy)methyl)tetrahydro-1H-thiophen-1-ium-1-yl)-1,3-dihydroxybutan-2-ylsulfate as a white solid.

¹H-NMR (DMSO-D₆) δ values: 3.61-3.65 (2H, m), 3.74-4.05 (6H, m),4.09-4.14 (1H, m), 4.17-4.23 (1H, m), 4.36-4.41 (1H, m), 4.50-4.80 (9H,m), 6.01 (1H, d, J=6.0 Hz), 7.23-7.39 (15H, m).

Example 8

24 mg of 20% palladium hydroxide/carbon was added to 1 mL of acetic acidsolution containing 240 mg of(2S,3S)-4-((1R,2R,3S,4S)-3,4-(bis(benzyloxy)-2-((benzyloxy)methyl)tetrahydro-1H-thiophen-1-ium-1-yl)-1,3-dihydroxybutan-2-ylsulfate at 25° C., followed by stirring for 2 hours at 50° C. in ahydrogen atmosphere. The reaction mixture was cooled to roomtemperature, and insoluble matters were removed by filtration.

As a result of measuring ¹H-NMR and HPLC, it was confirmed that the rawmaterial disappeared, and salacinol was generated.

Example 9

18 μL of 2,6-lutidine was added to 1 mL of an acetone solutioncontaining 1.00 g of(2R,3S,4S)-3,4-(bis((4-methoxybenzyl)oxy)-2-(((4-methoxybenzyl)oxy)methyl)tetrahydrothiopheneand 671 mg of dimethyl2-((4aR,8aS)-2,2-dioxidotetrahydro[1,3]dioxino[5,4-d][1,3,2]dioxathiin-6-yl)malonateat 25° C., followed by stirring for 13 hours at 70° C. The reactionmixture was cooled to room temperature, and the solvent was distilledaway under reduced pressure. The obtained residue was purified by columnchromatography (chloroform/methanol=90/10), thereby obtaining 1.10 g of(4S,5S)-4-(((1S,2R,3S,4S)-3,4-bis((4-methoxybenzyl)oxy)-2-(((4-methoxybenzyl)oxy)methyl)tetrahydro-1H-thiophen-1-ium-1-yl)methyl)-2-(1,3-dimethoxy-1,3-dioxopropan-2-yl)-1,3-dioxan-5-ylsulfate as a white solid.

¹H-NMR (DMSO-D₆) δ values: 3.52-4.17 (25H, m), 4.21-4.28 (2H, m),4.41-4.58 (7H, m), 4.64-4.69 (1H, m), 5.16 (1H, d, J=7.5 Hz), 6.88-6.93(6H, m), 7.16-7.28 (6H, m).

Example 10

74 μL of diethylamide was added to 5.0 mL of a methanol solutioncontaining 500 mg of(4S,5S)-4-(((1S,2R,3S,4S)-3,4-bis((4-methoxybenzyl)oxy)-2-(((4-methoxybenzyl)oxy)methyl)tetrahydro-1H-thiophen-1-ium-1-yl)methyl)-2-(1,3-dimethoxy-1,3-dioxopropan-2-yl)-1,3-dioxan-5-ylsulfate at 25° C., followed by stirring for 3 hours at 25° C. Thesolvent of the reaction mixture was distilled away under reducedpressure, and the obtained residue was purified by column chromatography(chloroform/methanol=100/0 to 94/6), thereby obtaining 300 mg of(2S,3S)-4-(((1R,2R,3S,4S)-3,4-bis((4-methoxybenzyl)oxy)-2-(((4-methoxybenzyl)oxy)methyl)tetrahydro-1H-thiophen-1-ium-1-yl)-1,3-dihydroxybutan-2-ylsulfate as a white solid.

¹H-NMR (DMSO-D₆) δ values: 3.49-3.99 (17H, m), 4.06-4.21 (2H, m),4.28-4.31 (1H, m), 4.38-4.66 (8H, m), 4.76-4.79 (1H, m), 6.00 (1H, d,J=6.0 Hz), 6.30-6.93 (6H, m), 7.16-7.28 (6H, m).

Example 11

A mixed solution of 1.2 mL of trifluoroacetic acid and 0.2 L of watercontaining 300 mg of(2S,3S)-4-(((1R,2R,3S,4S)-3,4-bis((4-methoxybenzyl)oxy)-2-(((4-methoxybenzyl)oxy)methyl)tetrahydro-1H-thiophen-1-ium-1-yl)-1,3-dihydroxybutan-2-ylsulfate was stirred for 2 hours at 25° C.

As a result of measuring ¹H-NMR and HPLC, it was confirmed that the rawmaterial disappeared, and salacinol was generated.

Example 12

267 mg of tert-butoxypotassium was added to 50 mL of a tetrahydrofuransolution containing 5.00 g of(4S,5R)-4-(hydroxymethyl)-2-phenyl-1,3-dioxan-5-ol and 5.7 g of diethylethoxymethylene malonate at 25° C., followed by stirring for 1 hour at25° C. Toluene was added to the reaction mixture, tetrahydrofuran wasdistilled away under reduced pressure, and then ethyl acetate and waterwere added thereto. An organic layer was collected by separation, washedsequentially with water and a saturated aqueous sodium chloridesolution, and dried over anhydrous magnesium sulfate, and the solventwas distilled away under reduced pressure. The obtained residue waspurified by column chromatography (hexane/ethyl acetate=16/84 to 33/67),thereby obtaining 3.54 g of diethyl2-((4aS,8aR)-6-phenyltetrahydro[1,3]dioxino[5,4-d][1,3]dioxin-2-yl)malonateas a white solid.

¹H-NMR (CDCl₃) δ values: 1.24-1.31 (6H, m), 3.65 (1H, d, J=7.8 Hz),3.65-3.82 (4H, m), 4.19-4.27 (6H, m), 5.30 (1H, d, J=7.8 Hz), 5.61 (1H,s), 7.35-7.39 (3H, m), 7.45-7.49 (2H, m).

Example 13

800 μL of a 0.5 mol/L hydrochloric acid/methanol solution to 18 mL of amethanol solution containing 3.54 g of diethyl2-((4aS,8aR)-6-phenyltetrahydro[1,3]dioxino[5,4-d][1,3]dioxin-2-yl)malonateat 25° C., followed by stirring for 3 hours at 25° C. 50 μLtriethylamine was added to the reaction mixture, and the solvent wasdistilled away under reduced pressure. The obtained residue was purifiedby column chromatography (hexane/ethyl acetate=33/67 to 0/100), therebyobtaining 2.45 g of diethyl2-((4R,5S)-5-hydroxy-4-(hydroxymethyl)-1,3-dioxan-2-yl)malonate as acolorless oily substance.

¹H-NMR (CDCl₃) δ values: 1.24-1.30 (6H, m), 2.37 (1H, s), 2.75 (1H, s),3.44-3.56 (2H, m), 3.63 (1H, d, J=7.5 Hz), 3.78-3.86 (3H, m), 4.16-4.26(5H, m), 5.15 (1H, d, J=7.5 Hz).

Example 14

4.44 mL of triethylamine was added to 40 mL of a methylene chloridesolution containing 2.45 g of diethyl2-((4R,5S)-5-(hydroxy-4-(hydroxymethyl)-1,3-dioxan-2-yl)malonate at atemperature of equal to or lower than −5° C., and then 21 mL of amethylene chloride solution containing 913 μL of thionyl chloride wasadded dropwise thereto at a temperature of equal to or lower than −5° C.The reaction mixture was stirred for 20 minutes at a temperature ofequal to or lower than 5° C., water was added thereto. An organic layerwas collected by separation and then washed sequentially with 1 mol/Lhydrochloric acid, a saturated aqueous sodium hydrogen carbonatesolution, and a saturated aqueous sodium chloride solution, and thesolvent was distilled away under reduced pressure.

A mixed solution of 10 mL of methylene chloride and 10 mL of acetontrilecontaining the obtained residue was added dropwise to 25 mL of anaqueous solution containing 6.64 g of sodium periodate and 52.2 mg ofruthenium (III) chloride n-hydrate at 0° C., followed by stirring for 20minutes. Ethyl acetate was added to the reaction mixture. An organiclayer was collected by separation and washed sequentially with water, a10% aqueous sodium thiosulfate solution, and a saturated aqueous sodiumchloride solution, and anhydrous magnesium sulfate and silica gel wereadded thereto, followed by stirring for 5 minutes. After insolublematters were removed by filtration, the solvent was distilled away underreduced pressure. The obtained residue was purified by columnchromatography (hexane/ethyl acetate=84/16 to 60/40), thereby obtaining2.10 g of diethyl2-((4aR,8aS)-2,2-dioxidotetrahydro[1,3]dioxino[5,4-d][1,3,2]dioxathiin-6-yl)malonateas a white solid.

¹H-NMR (CDCl₃) δ values: 1.25-1.30 (6H, m), 3.65 (1H, d, J=7.8 Hz), 3.80(1H, dd, J=10.5, 10.5 Hz), 4.02-4.11 (1H, m), 4.18-4.35 (5H, m),4.52-4.57 (1H, m), 4.63-4.72 (2H, m), 5.26 (1H, d, J=7.8 Hz).

Example 15

31 μL of 2,6-lutidine was added to 1.5 mL of an acetone solutioncontaining 500 mg of(2R,3S,4S)-2-(hydroxymethyl)tetrahydrothiophene-3,4-diol and 1.24 g ofdiethyl2-((4aR,8aS)-2,2-dioxidotetrahydro[1,3]dioxino[5,4-d][1,3,2]dioxathiin-6-yl)malonateat 25° C., followed by stirring for 13 hours at 70° C. The reactionmixture was cooled to room temperature, acetone was added thereto, andsolids were collected by filtration, thereby obtaining 1.01 g of(4S,5S)-2-(1,3-diethoxy-1,3-dioxopropan-2-yl)-4-(((2R,3S,4S)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-ium-1-yl)methyl)-1,3-dioxan-5-ylsulfate as a white solid. As a result of measuring ¹H-NMR, it wasconfirmed that a ratio of trans/cis in this compound was 81/19.

¹H-NMR (DMSO-D₆) δ values: 1.19 (6H, dd, J=7.0, 13.6 Hz), 3.54-4.21(17H, m), 4.45-4.51 (1H, m), 5.20 (1H, m), 5.68-5.71 (1H, m), 6.12-6.14(2H, m).

Example 16

123 μL of diethylamine was added to a mixed solution of 2.5 mL of waterand 2.5 mL of ethyl acetate containing 500 mg of(4S,5S)-2-(1,3-diethoxy-1,3-dioxopropan-2-yl)-4-(((2R,3S,4S)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-ium-1-yl)methyl)-1,3-dioxan-5-ylsulfate (trans/cis=81/19) at 25° C., followed by stirring for 9 hours at25° C. An aqueous layer was collected by separation and washed withethyl acetate, and the solvent was distilled away under reducedpressure.

As a result of measuring ¹H-NMR and HPLC of the obtained residue, it wasconfirmed that salacinol was generated, and the reaction rate was 97%.

Example 17

22.0 mL of acetyl chloride was added dropwise to 840 mL of a methanolsolution containing 120 g of(3R,4R,5R)-5-(hydroxymethyl)tetrahydrofuran-2,3,4-triol at a temperatureof equal to or lower than 10° C., followed by stirring for 2 hours at atemperature of 20° C. to 30° C. 63 mL of a 28% sodium methoxide/methanolsolution was added to the reaction mixture, methanol was distilled awayunder reduced pressure, and 800 mL of acetonitrile and 480 g ofp-toluenesulfonyl chloride were added thereto. In a state where theinternal temperature was kept at a temperature of equal to or lower than25° C., a mixture of 323 mL of triethylamine and 25.2 mL ofN-methylimidazole was added dropwise thereto, followed by stirring for2.5 hours at 30° C. 900 mL of water was added to the reaction mixture,followed by stirring for 2 hours at 30° C., and ethyl acetate was addedthereto. An organic layer was collected by separation, washed with a 25%aqueous sodium chloride solution, and dried over anhydrous magnesiumsulfate, and the solvent was removed under reduced pressure. 1.91 L ofethanol was added to the obtained residue and dissolved by heating, andthe resulting mixture was crystallized while being cooled. 800 mL ofmethanol was added thereto at an internal temperature of 35° C.,followed by stirring for 2 hours at 25° C. Solids were collected byfiltration, thereby obtaining 47 g of(3R,4S,5R)-2-methoxy-5-(((4-methylphenyl)sulfonyloxy)methyl)tetrahydrofuran-3,4-diylbis(4-methylbenzenesulfonate) as a white solid.

¹H-NMR (CDCl₃) δ values: 7.77-7.64 (6H, m), 7.41-7.32 (6H, m), 5.04(0.26H, t, J=6.9 Hz), 4.79 (0.74H, dd, J=1.2, 6.0 Hz), 4.80-4.65 (2H,m), 4.43 (0.74H, m), 4.34 (0.26H, m), 4.25-4.19 (0.26H, m), 4.12-4.04(1.74H, m), 3.21 (0.78H, s), 3.16 (2.22H, s), 2.48-2.45 (3H, m).

Example 18

65.0 g of S-potassium thioacetate was added to 585 mL of aN,N-dimethylformamide solution containing 200 g of(3R,4S,5R)-2-methoxy-5-(((4-methylphenyl)sulfonyloxy)methyl)tetrahydrofuran-3,4-diylbis(4-methylbenzenesulfonate) in a nitrogen atmosphere, followed bystirring for 2 hours at 70° C. The reaction mixture was cooled to roomtemperature, and water, a 25% aqueous sodium chloride solution, andethyl acetate were added thereto. An organic layer was collected byseparation, washed sequentially with a 7.5% aqueous sodium hydrogencarbonate solution, 1 mol/L hydrochloric acid, and a 25% aqueous sodiumchloride solution, treated with 3 g of activated carbon, and then driedover anhydrous magnesium sulfate, and the solvent was distilled awayunder reduced pressure. As a result, 161.5 g ofS-(((2S,3S,4R)-5-methoxy-3,4-bis((4-methylphenyl)sulfonyloxy)tetrahydrofuran-2-yl)methyl)ethanethioate as a reddish brown oily substance was obtained.

¹H-NMR (CDCl₃) δ values: 7.79-7.69 (4H, m), 7.40-7.32 (4H, m), 5.04-4.75(3H, m), 4.33-4.26 (1H, m), 3.24 (2.13H, s), 3.22 (0.87H, s), 3.19-2.98(2H, m), 2.75-2.45 (6H, m), 2.31 (0.87H, s), 2.29 (2.13H, s).

Example 19

30.2 g of potassium carbonate was added to 463 mL of a methanol solutioncontaining 119 g ofS-(((2S,3S,4R)-5-methoxy-3,4-bis((4-methylphenyl)sulfonyloxy)tetrahydrofuran-2-yl)methyl)ethanethioate in a nitrogen atmosphere, followed by stirring for 1 hourat 25° C. and then for 1 hour at 60° C. The reaction mixture was cooledto 15° C., and 170 g of a 50% aqueous sodium hydroxide solution wasadded dropwise thereto at a temperature of equal to or lower than 25° C.The reaction mixture was stirred for 1 hour at 60° C. and then cooled to10° C. Insoluble matters were removed by filtration, and the solvent wasdistilled away under reduced pressure. Toluene was added to the obtainedresidue, and the solvent was distilled away under reduced pressure,thereby obtaining 35.4 g of(1S,4S,7S)-3-methoxy-2-oxa-5-thiabicyclo[2.2.1]heptan-7-ol as a reddishbrown oily substance.

213 mL of toluene, 1.82 g of tetrabutylammonium chloride, and 70.4 g ofa 50% aqueous sodium hydroxide solution were added to the obtained(1S,4S,7S)-3-methoxy-2-oxa-5-thiabicyclo[2.2.1]heptan-7-ol. The mixturewas cooled to 10° C. and stirred, and then 37.1 g. of p-toluenesulfonylchloride was added dropwise thereto in a state where the internaltemperature was kept at a temperature of equal to or lower than 15° C.The mixture was heated to 25° C., and water and toluene were addedthereto, followed by stirring for 3 hours at 25° C. Toluene and waterwere added to the reaction mixture. An organic layer was collected byseparation, washed with a 25% aqueous sodium chloride solution, treatedwith 3 g of activated carbon, and then dried over anhydrous magnesiumsulfate, and the solvent was distilled away under reduced pressure. As aresult 38.6 g of(1S,4S,7S)-3-methoxy-2-oxa-5-thiabicyclo[2.2.1]heptan-7-yl4-methylbenzoate as an orange oily substance was obtained.

¹H-NMR (CDCl₃) δ values: 7.94-7.89 (2H, m), 7.27-7.22 (2H, m), 5.58(0.37H, t), 5.43 (0.63H, t), 5.34 (0.63H, d, J=2.4 Hz), 4.97 (0.37H, s),4.74-4.71 (0.37H, m), 4.67-4.65 (0.63H, m), 3.81 (0.63H, t, J=2.4 Hz),3.59 (0.37H, d, J=2.4 Hz), 3.54 (1.89H, s), 3.40 (1.11H, s), 3.09(1.26H, d, J=1.5 Hz), 3.02-2.91 (0.74H, m), 2.41 (3H, s).

Example 20

77 mL of 2 mol/L hydrochloric acid was added to 386 mL of atetrahydrofuran solution containing 38.6 g of(1S,4S,7S)-3-methoxy-2-oxa-5-thiabicyclo[2.2.1]heptan-7-yl4-methylbenzoate, followed by stirring for 1 hour at 50° C. The reactionmixture was cooled to 5° C., 15.6 g of sodium hydrogen carbonate wasadded thereto, and then 10.4 g of sodium borohydride was added theretoin a state where the internal temperature was kept at a temperature ofequal to or lower than 20° C. The reaction mixture was stirred for 10minutes at a temperature of equal to or lower than 20° C. and thenstirred for 1.5 hours at 25° C. The reaction mixture was cooled to 5°C., and 75 mL of 6 mol/L of hydrochloric acid was added dropwise theretoin a state where the internal temperature was kept at a temperature ofequal to or lower than 20° C. Ethyl acetate and water were added to thereaction mixture. An organic layer was collected by separation, washedsequentially with a 25% aqueous sodium chloride solution, a mixedsolution of a 7.5% aqueous sodium hydrogen carbonate solution and a 25%aqueous sodium chloride solution, and a 25% aqueous sodium chloridesolution, and dried over anhydrous magnesium sulfate, and the solventwas distilled away under reduced pressure. 50 mL of ethyl acetate wasadded to the obtained residue and dissolved by heating, and then 100 mLof hexane was added thereto. Solids were collected by filtration,thereby obtaining 12.2 g of(2R,3S,4S)-4-hydroxy-2-(hydroxymethyl)tetrahydrothiophen-3-yl4-methylbenzoate as a white solid.

¹H-NMR (CDCl₃) δ values: 7.90 (2H, d, J=7.8 Hz), 7.25 (2H, d, J=7.8 Hz),5.37 (1H, t, J=2.7 Hz), 4.55-4.47 (1H, m), 4.15-4.06 (1H, m), 4.03-3.97(1H, m), 3.79-3.73 (1H, m), 3.69-3.66 (1H, m), 3.34-3.28 (1H, m),3.08-3.02 (1H, m), 2.91 (1H, br), 2.42 (3H, s).

Example 21

2.68 g of (2R,3S,4S)-4-hydroxy-2-(hydroxymethyl)tetrahydrothiophen-3-yl4-methylbenzoate was dissolved in a mixed solution of 15 mL of methanoland 10 mL of tetrahydrofuran, and 58 mg of a 28% sodiummethoxide/methanol solution was added thereto, followed by stirring for4 hours at room temperature. The solvent was distilled away underreduced pressure. Ethyl acetate and water were added to the obtainedresidue. An aqueous layer was collected by separation and washed withethyl acetate. An organic layer was extracted using water. The aqueouslayer and the extract liquid were mixed together, and water wasdistilled away under reduced pressure, thereby obtaining 1.48 g of(2R,3S,4S)-2-hydroxymethyl)tetrahydrothiophene-3,4-diol as a colorlessoily substance.

¹H-NMR (DMSO-D₆) δ values: 5.12 (1H, d, J=4.5 Hz), 5.08 (1H, d, J=4.5Hz), 4.82 (1H, t) 3.99-3.92 (1H, m), 3.76-3.68 (2H, m), 3.39-3.31 (1H,m), 3.11-3.04 (1H, m), 2.91-2.84 (1H, m), 2.59-2.52 (1H, m).

Example 22

2.4 g of tert-butoxypotassium was added to 50 mL of a tetrahydrofuransolution containing 10 g of 1-phenylethane-1,2-diol and 10.2 g ofdimethyl methoxymethylene malonate at 25° C., followed by stirring for5.5 hours at 25° C. 40 mL of toluene was added to the reaction mixture,tetrahydrofuran was distilled away under reduced pressure, and thenethyl acetate and water were added thereto. An organic layer wascollected by separation, washed sequentially with water, 1 mol/Lhydrochloric acid, and a saturated aqueous sodium chloride solution, anddried over anhydrous magnesium sulfate, and the solvent was distilledaway under reduced pressure. The obtained residue was purified by columnchromatography, thereby obtaining 6.2 g of dimethyl2-(4-phenyl-1,3-dioxolan-2-yl)malonate as a colorless oily substance.

¹H-NMR (CDCl₃) δ values: 7.39-7.33 (5H, m) 5.90 (0.5H, d, J=6.9 Hz),5.73 (0.5H, d, J=6.9 Hz), 5.11 (1H, m), 4.44-4.25 (1H, m), 3.80-3.78(6H, m), 3.77-3.72 (2H, m).

Example 23

(23-1)

146 mg of diethylamine was added to a solution of 2 mL ethyl acetate and2 mL of water containing 280 mg of dimethyl2-(4-phenyl-1,3-dioxolan-2-yl)malonate at 25° C., followed by stirringfor 2 hours at 25° C. An organic layer was collected by separation,washed sequentially with water, 1 mol/L hydrochloric acid, and asaturated aqueous sodium chloride solution, and dried over anhydrousmagnesium sulfate, and the solvent was distilled away under reducedpressure.

As a result of measuring ¹H-NMR of the obtained residue, it wasconfirmed that 1-phenylethane-1,2-diol was generated, and the reactionrate was 96%.

(23-2)

232 mg of a 28% sodium methoxide/methanol solution was added to 2 mL ofa methanol solution containing 280 mg of dimethyl2-(4-phenyl-1,3-dioxolan-2-yl)malonate at 25° C., followed by stirringfor 3 hours at 25° C. Ethyl acetate and water were added to the reactionmixture. An organic layer was collected by separation, washedsequentially with water, 1 mol/L hydrochloric acid, and a saturatedaqueous sodium chloride solution, and dried over anhydrous magnesiumsulfate, and the solvent was distilled away under reduced pressure.

As a result of measuring ¹H-NMR of the obtained residue, it wasconfirmed that 1-phenylethane-1,2-diol was generated, and the reactionrate was 100%.

(23-3)

166 mg of potassium carbonate was added to 2 mL of a methanol solutioncontaining 280 mg of dimethyl 2-(4-phenyl-1,3-dioxolan-2-yl)malonate at25° C., followed by stirring for 3 hours at 25° C. Ethyl acetate andwater were added to the reaction mixture. An organic layer was collectedby separation, washed sequentially with water, 1 mol/L hydrochloricacid, and a saturated aqueous sodium chloride solution, and dried overanhydrous magnesium sulfate, and the solvent was distilled away underreduced pressure.

As a result of measuring ¹H-NMR of the obtained residue, it wasconfirmed that 1-phenylethane-1,2-diol was generated, and the reactionrate was 93%.

(23-4)

100 mg of a sodium hydrogen carbonate was added to 2 mL of a methanolsolution containing 280 mg of dimethyl2-(4-phenyl-1,3-dioxolan-2-yl)malonate at 25° C., followed by stirringfor 3 hours at 25° C. Ethyl acetate and water were added to the reactionmixture. An organic layer was collected by separation, washedsequentially with water, 1 mol/L hydrochloric acid, and a saturatedaqueous sodium chloride solution, and dried over anhydrous magnesiumsulfate, and the solvent was distilled away under reduced pressure.

As a result of measuring ¹H-NMR of the obtained residue, it wasconfirmed that 1-phenylethane-1,2-diol was generated, and the reactionrate was 92%.

The compound of the present invention is useful as an intermediate formanufacturing salacinol useful as a bioactive substance, and themanufacturing method of the present invention is useful as a method formanufacturing salacinol.

What is claimed is:
 1. A method for manufacturing a compound representedby Formula (7b), comprising:

obtaining a compound represented by Formula (12) by reacting a compoundrepresented by Formula (10) with a compound represented by Formula (11),

(in the formula, R⁷ is a C1-3 alkyl group which may be substituted),R^(4ba)-L¹  (11) (in the formula, R^(4ba) is a p-toluoyl group; and L¹is a leaving group), and

(in the formula, each of R^(4ba) and R⁷ has the same definition asdescribed above); then obtaining a compound represented by Formula (7a)by reacting the compound represented by Formula (12) with an acid andthen subjecting the resulting compound to a reduction reaction,

(in the formula, R^(4ba) has the same definition as described above);and then subjecting the compound represented by Formula (7a) to adeprotection reaction.
 2. A method for manufacturing a compoundrepresented by Formula (7b), comprising:

obtaining a compound represented by Formula (15) by reacting a compoundrepresented by Formula (13) with a compound represented by Formula (14),

(in the formula, R⁷ is a C₁₋₃ alkyl group which may be substituted),R⁸-L²  (14) (in the formula, R⁸ is a C₁₋₃ alkylsulfonyl group which maybe substituted or an arylsulfonyl group which may be substituted; and L²is a leaving group), and

(in the formula, each of R⁷ and R⁸ has the same definition as describedabove); then obtaining a compound represented by Formula (17) byreacting the compound represented by Formula (15) with a compoundrepresented by Formula (16),R⁹—S⁻K⁺  (16) (in the formula, R⁹ is an acyl group which may besubstituted), and

(in the formula, each of R⁷, R⁸, and R⁹ has the same definition asdescribed above); then obtaining a compound represented by Formula (18)by reacting the compound represented by Formula (17) with a base,

(in the formula, each of R⁷ and R⁸ has the same definition as describedabove); then obtaining a compound represented by Formula (10) bysubjecting the compound represented by Formula (18) to a deprotectionreaction,

(in the formula, R⁷ has the same definition as described above); thenobtaining a compound represented by Formula (12) by reacting thecompound represented by Formula (10) with a compound represented byFormula (11),R^(4ba)-L¹  (11) (in the formula, R^(4ba) is a p-toluoyl group; and L¹is a leaving group), and

(in the formula, each of R^(4ba) and R⁷ has the same definition asdescribed above); then obtaining a compound represented by Formula (7a)by reacting the compound represented by Formula (12) with an acid andthen subjecting the resulting compound to a reduction reaction,

(in the formula, R^(4ba) has the same definition as described above);and then subjecting the compound represented by Formula (7a) to adeprotection reaction.
 3. A method for protecting a 1,2-diol group or a1,3-diol group, comprising reacting a 1,2-diol group or a 1,3-diol groupwith a group represented by Formula (19) in the presence of a base,

(in the formula, R^(1a) and R^(1b) are the same as or different fromeach other and each represent a hydrogen atom or a carboxy protectivegroup; and * is a binding position).
 4. A method for protecting a1,2-diol group or a 1,3-diol group, comprising manufacturing a compoundrepresented by Formula (21) by reacting a 1,2-diol group or a 1,3-diolgroup of a compound represented by Formula (20) with a compoundrepresented by Formula (9) in the presence of a base,HO—Y¹—OH  (20) (in the formula, Y¹ is a C₂₋₃ alkylene group which may besubstituted),

(in the formula, each of R^(1a) and R^(1b) are the same as or differentfrom each other and each represent a hydrogen atom or a carboxyprotective group; and R⁶ is a C₁₋₆ alkyl group which may besubstituted), and

(in the formula, each of R^(1a), R^(1b), and Y¹ has the same definitionas described above).
 5. A protective agent for a 1,2-diol group or a1,3-diol group, which is a compound represented by Formula (9),

(in the formula, R^(1a) and R^(1b) are the same as or different fromeach other and each represent a hydrogen atom or a carboxy protectivegroup; and R⁶ is a C₁₋₆ alkyl group which may be substituted).
 6. Amethod for deprotecting a protected 1,2-diol group or 1,3-diol group,comprising protecting a 1,2-diol group or a 1,3-diol group with a grouprepresented by Formula (19) according to the method of claim 3; andreacting the 1,2-diol group or a 1,3-diol group protected with a grouprepresented by Formula (19) with a base,

(in the formula, R^(1a) and R^(1b) are the same as or different fromeach other and each represent a hydrogen atom or a carboxy protectivegroup; and * is a binding position).
 7. A method for deprotecting aprotected 1,2-diol group or 1,3-diol group, comprising manufacturing acompound represented by Formula (21) according to the method of claim 4;and manufacturing a compound represented by Formula (20) by reacting thecompound which is represented by Formula (21) and has a protected1,2-diol group or a protected 1,3-diol group with a base,

(in the formula, R^(1a) and R^(1b) are the same as or different fromeach other and each represent a hydrogen atom or a carboxy protectivegroup; and Y¹ is a C₂₋₃ alkylene group which may be substituted), andHO—Y¹—OH  (20) (in the formula, Y¹ has the same definition as describedabove).